MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

ABSTRACT

Compounds useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4) and use thereof.

BACKGROUND

The amino acid L-glutamate (referred to herein simply as glutamate) isthe principal excitatory neurotransmitter in the mammalian centralnervous system (CNS). Within the CNS, glutamate plays a key role insynaptic plasticity (e.g., long term potentiation (the basis of learningand memory)), motor control and sensory perception. It is now wellunderstood that a variety of neurological and psychiatric disorders,including, but not limited to, schizophrenia general psychosis andcognitive deficits, are associated with dysfunctions in theglutamatergic system. Thus, modulation of the glutamatergic system is animportant therapeutic goal. Glutamate acts through two distinctreceptors: ionotropic and metabotropic glutamate receptors. The firstclass, the ionotropic glutamate receptors, is comprised of multi-subunitligand-gated ion channels that mediate excitatory post-synapticcurrents. Three subtypes of ionotropic glutamate receptors have beenidentified, and despite glutamate serving as agonist for all threereceptor subtypes, selective ligands have been discovered that activateeach subtype. The ionotropic glutamate receptors are named after theirrespective selective ligands: kainate receptors, AMPA receptors and NMDAreceptors.

The second class of glutamate receptor, termed metabotropic glutamatereceptors, (mGluRs), are G-protein coupled receptors (GPCRs) thatmodulate neurotransmitter release or the strength of synaptictransmission, based on their location (pre- or post-synaptic). ThemGluRs are family C GPCR, characterized by a large (˜560 amino acid)“venus fly trap” agonist binding domain in the amino-terminal domain ofthe receptor. This unique agonist binding domain distinguishes family CGPCRs from family A and B GPCRs wherein the agonist binding domains arelocated within the 7-strand transmembrane spanning (7™) region or withinthe extracellular loops that connect the strands to this region. Todate, eight distinct mGluRs have been identified, cloned and sequenced.Based on structural similarity, primary coupling to intracellularsignaling pathways and pharmacology, the mGluRs have been assigned tothree groups: Group I (mGluR1 and mGluR5), Group II (mGluR2 and mGluR3)and Group III (mGluR4, mGluR6, mGluR7 and mGluR8). Group I mGluRs arecoupled through Gαq/11 to increase inositol phosphate and metabolism andresultant increases in intracellular calcium. Group I mGluRs areprimarily located post-synaptically and have a modualtory effect on ionchannel activity and neuronal excitability. Group II (mGluR2 and mGluR3)and Group III (mGluR4, mGluR6, mGluR7 and mGluR8) mGluRs are primarilylocated pre-synaptically where they regulate the release ofneurotransmitters, such as glutamate. Group II and Group III mGluRs arecoupled to Gαi and its associated effectors such as adenylate cyclase.

mGluR4 belongs to the group III mGluR subfamily and is located inpredominantly presynaptic locations in the central nervous system(Benitez et al., 2000; Bradley et al., 1996; Bradley et al., 1999;Mateos et al., 1998; Phillips et al., 1997) where it is functions as anauto- and heteroreceptor to regulate the release of both GABA andglutamate. mGluR4 has also been shown to be expressed at a low level insome postsynaptic locations (Benitez et al., 2000). Numerous reportsindicate that mGluR4 is expressed in most brain regions, particularly inneurons known to play key roles in functions of the basal ganglia(Bradley et al., 1999; Corti et al., 2002; Kuramoto et al., 2007; Marinoet al., 2003a), learning and memory (Bradley et al., 1996), vision(Akazawa et al., 1994; Koulen et al., 1996; Quraishi et al., 2007),cerebellar functions (Makoff et al., 1996), feeding and the regulationof hypothalamic hormones (Flor et al., 1995), sleep and wakefulness(Noriega et al., 2007) as well as many others. There are now a number ofliterature reports describing a role for mGluR4 modulation inParkinson's disease (Battaglia et al., 2006; Lopez et al., 2007; Marinoet al., 2005; Marino et al., 2003b; Ossowska et al., 2007; Valenti etal., 2003), anxiety (Stachowicz et al., 2006; Stachowicz et al., 2004),motor effects after alcohol consumption (Blednov et al., 2004),neurogenic fate commitment and neuronal survival (Saxe et al., 2007),epilepsy (Chapman et al., 2001; Pitsch et al., 2007; Snead et al., 2000;Wang et al., 2005) and cancer, particularly medulloblastoma (Iacovelliet al., 2004).

In addition, there is evidence that activation of mGluR4 receptors(expressed in islets of Langerhans) would inhibit glucagon secretion(Uehara et al., 2004). Thus, activation of mGluR4 may be an effectivetreatment for disorders involving defects in glucose metabolism suchashypoglycemia, Type 2 diabetes, and obesity.

Also, there are reports that activation of Group III mGluRs,specifically mGluR4, may be an effective treatment for neuroinflammatorydiseases, such as multiple sclerosis and related disorders (Besong etal., 2002).

There are two variants of the mGluR4 receptor which are expressed intaste tissues; and thus activation of mGluR4 may be used as tasteenhancers, blockade of certain tastes, or taste agents, flavoring agentsor other food additives (Kurihara, 2009; Chaudhari et al, 2009).

Despite advances in mGluR4 research, there is still a scarcity ofcompounds that effectively potentiate mGluR4 which are also effective inthe treatment of neurological and psychiatric disorders associated withglutamatergic neurotransmission dysfunction and diseases, as well asinflammatory central nervous system disorders, medulloblastomas,metabolic disorders and taste enhancing associated with glutamatergicdysfunction and diseases in which mGluR4 receptor is involved. Further,conventional mGluR4 receptor modulators typically lack satisfactoryaqueous solubility and exhibit poor oral bioavailability. These needsand other needs are satisfied by the present invention.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompounds useful as allosteric modulators of mGluR4 receptor activity,methods of making same, pharmaceutical compositions comprising same, andmethods of treating neurological and psychiatric disorders associatedwith glutamate dysfunction, for example Parkinson's disease, using same.Further disclosed are methods and pharmaceutical compositions useful fortreating a disease related to mGluR4 activity. In one aspect, thedisclosed compounds can affect the sensitivity of mGluR4 receptors toagonists without binding to the orthosteric agonist binding site oracting as orthosteric agonists themselves.

Disclosed are methods for the treatment of a neurotransmissiondysfunction or other disease state associated with mGluR4 activity in amammal comprising the step of administering to the mammal at least onecompound in a dosage and amount effective to treat the dysfunction inthe mammal, the compound having a structure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof.

Also disclosed are methods for potentiating mGluR4 activity in a subjectcomprising the step of administering to the subject at least onecompound in a dosage and amount effective to potentiate mGluR4 activityin the subject, the compound having a structure represented by aformula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof, in a dosage and amount effective topotentiate mGluR4 receptor activity in the subject.

Also disclosed are methods of potentiating mGluR4 activity in at leastone cell comprising the step of contacting the at least one cell with atleast one compound in an amount effective to potentiate mGluR4 receptoractivity in the at least one cell, the at least one compound having astructure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof, in an amount effective to potentiatemGluR4 receptor activity in the at least one cell.

Also disclosed are compounds having a structure represented by aformula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a compound having a structurerepresented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof; and a pharmaceutically acceptablecarrier.

Also disclosed are methods for potentiating mGluR4 activity in at leastone cell comprising the step of contacting at least one cell with atleast one disclosed compound in an amount effective to potentiate mGluR4receptor activity in at least one cell.

Also disclosed are methods for potentiating mGluR4 activity in a subjectcomprising the step of administering to the subject a therapeuticallyeffective amount of at least one disclosed compound in a dosage andamount effective to potentiate mGluR4 receptor activity in the subject.

Also disclosed are methods for the treatment of a disorder associatedwith mGluR4 neurotransmission dysfunction or other mGluR4 mediateddisease states in a mammal comprising the step of administering to themammal at least one disclosed compound in a dosage and amount effectiveto treat the disorder in the mammal.

Also disclosed are methods for making a compound comprising the steps ofproviding an amine compound having a structure represented by a formula:

as shown in the Examples below.

Also disclosed are the products of the disclosed methods of making.

Also disclosed are methods for the manufacture of a medicament forpotentiating mGluR4 receptor activity in a mammal comprising combining acompound having a structure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof with a pharmaceutically acceptablecarrier.

Also disclosed are the products of the disclosed methods for themanufacture of a medicament.

Also disclosed are uses of a compound for potentiating mGluR4 receptoractivity in a mammal, wherein the compound has a structure representedby a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof.

Also disclosed are methods for the treatment of a neurotransmissiondysfunction and other disease states associated with mGluR4 activity ina mammal comprising the step of co-administering to the mammal at leastone compound in a dosage and amount effective to treat the dysfunctionin the mammal, the compound having a structure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof with a drug having a known side-effect ofincreasing metabotropic glutamate receptor activity.

Also disclosed are methods for the treatment of a neurotransmissiondysfunction and other disease states associated with mGluR4 activity ina mammal comprising the step of co-administering to the mammal at leastone compound in a dosage and amount effective to treat the dysfunctionin the mammal, the compound having a structure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof with a drug known to treat a disorderassociated with increasing metabotropic glutamate receptor activity.

Also disclosed are methods for the treatment of a neurotransmissiondysfunction and other disease states associated with mGluR4 activity ina mammal comprising the step of co-administering to the mammal at leastone compound in a dosage and amount effective to treat the dysfunctionin the mammal, the compound having a structure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof with a drug known to treat theneurotransmission dysfunction or other disease states.

Also disclosed are kits comprising a compound having a structurerepresented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof, and one or more of a drug having a knownside-effect of increasing metabotropic glutamate receptor activity, adrug known to treat a disorder associated with increasing metabotropicglutamate receptor activity, and/or a drug known to treat theneurotransmission dysfunction.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance may or may not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “receptor positive allosteric modulator” refersto any exogenously administered compound or agent that directly orindirectly augments the activity of the receptor in the presence or inthe absence of the endogenous ligand (such as glutamate) in an animal,in particular a mammal, for example a human. The term “receptor positiveallosteric modulator” includes a compound that is a “receptor allostericpotentiator” or a “receptor allosteric agonist,” as well as a compoundthat has mixed activity as both a “receptor allosteric potentiator” andan “mGluR receptor allosteric agonist.”

As used herein, the term “receptor allosteric potentiator” refers to anyexogenously administered compound or agent that directly or indirectlyaugments the response produced by the endogenous ligand (such asglutamate) when it binds to an allosteric site of the receptor in ananimal, in particular a mammal, for example a human. The receptorallosteric potentiator binds to a site other than the orthosteric site(an allosteric site) and positively augments the response of thereceptor to an agonist. Because it does not induce desensitization ofthe receptor, activity of a compound as a receptor allostericpotentiator provides advantages over the use of a pure receptorallosteric agonist. Such advantages can include, for example, increasedsafety margin, higher tolerability, diminished potential for abuse, andreduced toxicity.

As used herein, the term “receptor allosteric agonist” refers to anyexogenously administered compound or agent that directly augments theactivity of the receptor in the absence of the endogenous ligand (suchas glutamate) in an animal, in particular a mammal, for example a human.The receptor allosteric agonist binds to the allosteric glutamate siteof the receptor and directly influences the orthosteric site of thereceptor.

As used herein, the term “subject” refers to a target of administration.The subject of the herein disclosed methods can be a vertebrate, such asa mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subjectof the herein disclosed methods can be a human, non-human primate,horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.The term does not denote a particular age or sex. Thus, adult andnewborn subjects, as well as fetuses, whether male or female, areintended to be covered. A patient refers to a subject afflicted with adisease or disorder. The term “patient” includes human and veterinarysubjects.

In some aspects of the disclosed methods, the subject has been diagnosedwith a need for treatment of one or more neurological and/or psychiatricdisorder and/or any other disease state associated with glutamatedysfunction prior to the administering step. In some aspects of thedisclosed method, the subject has been diagnosed with a need forpotentiation of metabotropic glutamate receptor activity prior to theadministering step. In some aspects of the disclosed method, the subjecthas been diagnosed with a need for partial agonism of metabotropicglutamate receptor activity prior to the administering step. In someaspects, the disclosed methods can further comprise a step ofidentifying a subject having a need for treatment of a discloseddisorder.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder.

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with a disorder treatable by potentiation of mGluR4 activity”means having been subjected to a physical examination by a person ofskill, for example, a physician, and found to have a condition that canbe diagnosed or treated by a compound or composition that can favorablypotentiate mGluR4 activity. As a further example, “diagnosed with a needfor potentiation of mGluR4 activity” refers to having been subjected toa physical examination by a person of skill, for example, a physician,and found to have a condition characterized by abnormal mGluR4 activity.Such a diagnosis can be in reference to a disorder, such as Parkinson'sdisease, and the like, as discussed herein.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto mGluR4 activity) based upon an earlier diagnosis by a person of skilland thereafter subjected to treatment for the disorder. It iscontemplated that the identification can, in one aspect, be performed bya person different from the person making the diagnosis. It is alsocontemplated, in a further aspect, that the administration can beperformed by one who subsequently performed the administration.

As used herein, the term “diagnosed with a need for potentiation ofmetabotropic glutamate receptor activity” refers to having beensubjected to a physical examination by a person of skill, for example, aphysician, and found to have a condition that can be diagnosed ortreated by potentiation of metabotropic glutamate receptor activity.

As used herein, “diagnosed with a need for partial agonism ofmetabotropic glutamate receptor activity” means having been subjected toa physical examination by a person of skill, for example, a physician,and found to have a condition that can be diagnosed or treated bypartial agonism of metabotropic glutamate receptor activity.

As used herein, “diagnosed with a need for treatment of one or moreneurological and/or psychiatric disorder or any disease state associatedwith glutamate dysfunction” means having been subjected to a physicalexamination by a person of skill, for example, a physician, and found tohave one or more neurological and/or psychiatric disorder associatedwith glutamate dysfunction.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, and parenteral administration, including injectable suchas intravenous administration, intra-arterial administration,intramuscular administration, and subcutaneous administration.Administration can be continuous or intermittent. In various aspects, apreparation can be administered therapeutically; that is, administeredto treat an existing disease or condition. In further various aspects, apreparation can be administered prophylactically; that is, administeredfor prevention of a disease or condition.

As used herein, the term “effective amount” refers to an amount that issufficient to achieve the desired result or to have an effect on anundesired condition. For example, a “therapeutically effective amount”refers to an amount that is sufficient to achieve the desiredtherapeutic result or to have an effect on undesired symptoms, but isgenerally insufficient to cause adverse side affects. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration; the route of administration; the rate of excretion ofthe specific compound employed; the duration of the treatment; drugsused in combination or coincidental with the specific compound employedand like factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of a compound at levels lowerthan those required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration. Consequently, single dose compositions cancontain such amounts or submultiples thereof to make up the daily dose.The dosage can be adjusted by the individual physician in the event ofany contraindications. Dosage can vary, and can be administered in oneor more dose administrations daily, for one or several days. Guidancecan be found in the literature for appropriate dosages for given classesof pharmaceutical products. In further various aspects, a preparationcan be administered in a “prophylactically effective amount”; that is,an amount effective for prevention of a disease or condition.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. SuiTable 3nertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc.

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of from 1 to 24 carbon atoms, for example from 1 to 12carbons, from 1 to 8 carbons, from 1 to 6 carbons, or from 1 to 4carbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl,heptyl, octyl, nonyl, decyl, dode cyl, tetradecyl, hexadecyl, eicosyl,tetracosyl, and the like. The alkyl group can be cyclic or acyclic. Thealkyl group can be branched or unbranched. The alkyl group can also besubstituted or unsubstituted. For example, the alkyl group can besubstituted with one or more groups including, but not limited to,optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide,hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A“lower alkyl” group is an alkyl group containing from one to six (e.g.,from one to four) carbon atoms. One example of “alkyl” is C₁₋₆ alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” specifically refers to an alkyl group thatis substituted with one or more halide, e.g., fluorine, chlorine,bromine, or iodine. The term “alkoxyalkyl” specifically refers to analkyl group that is substituted with one or more alkoxy groups, asdescribed below. The term “alkylamino” specifically refers to an alkylgroup that is substituted with one or more amino groups, as describedbelow, and the like. When “alkyl” is used in one instance and a specificterm such as “alkylalcohol” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclo[3.1.0]hexyl,bicyclo[4.1.0]heptyl, bicyclo[5.1.0]octyl, bicyclo[6.1.0]nonyl,bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[5.2.0]nonyl,bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[2.2.1]heptyl,bicyclo[3.2.1]octyl, bicyclo[4.2.1]nonyl, bicyclo[2.2.2]octyl,bicyclo[3.2.2]nonyl, and bicyclo[3.3.1]nonyl, and the like. The term“heterocycloalkyl” is a type of cycloalkyl group as defined above, andis included within the meaning of the term “cycloalkyl,” where at leastone of the carbon atoms of the ring is replaced with a heteroatom suchas, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.Examples of heterocycloalkyl groups include, but are not limited to,oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, oxepane,oxocane, dioxirane, dioxetane, dioxolane, dioxane, dioxepane, dioxocane,thiirane, thietane, tetrahydrothiophene, tetrahydro-2H-thiopyran,thiepane, thiocane, dithiirane, dithietane, dithiolane, dithiane,dithiepane, dithiocane, oxathiirane, oxathietane, oxathiolane,oxathiane, oxathiepane, oxathiocane, aziridine, azetidine, pyrrolidone,piperidine, azepane, azocane, diaziridine, diazetidine, imidazolidine,piperazine, diazepane, diazocane, hexahydropyrimidine, triazinane,oxaziridine, oxazetidine, oxazolidine, morpholine, oxazepane, oxazocane,thiaziridine, thiazetidine, thiazolidine, thiomorpholine, thiazepane,and thiazocane.

The cycloalkyl group and heterocycloalkyl group can be substituted orunsubstituted. The cycloalkyl group and heterocycloalkyl group can besubstituted with one or more groups including, but not limited to,optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide,hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by a formula —(CH₂)_(a)—, where “a” is an integer of from 2to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro,silyl, sulfo-oxo, or thiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl,cyclononenyl, cyclononadienyl, norbornenyl, and the like. The term“heterocycloalkenyl” is a type of cycloalkenyl group as defined above,and is included within the meaning of the term “cycloalkenyl,” where atleast one of the carbon atoms of the ring is replaced with a heteroatomsuch as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.Examples of heterocycloalkenyl groups include, but are not limited to, amono-, di- or tri-unsaturated analog of a heterocycloalkyl selected fromoxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, oxepane,oxocane, dioxirane, dioxetane, dioxolane, dioxane, dioxepane, dioxocane,thiirane, thietane, tetrahydrothiophene, tetrahydro-2H-thiopyran,thiepane, thiocane, dithiirane, dithietane, dithiolane, dithiane,dithiepane, dithiocane, oxathiirane, oxathietane, oxathiolane,oxathiane, oxathiepane, oxathiocane, aziridine, azetidine, pyrrolidone,piperidine, azepane, azocane, diaziridine, diazetidine, imidazolidine,piperazine, diazepane, diazocane, hexahydropyrimidine, triazinane,oxaziridine, oxazetidine, oxazolidine, morpholine, oxazepane, oxazocane,thiaziridine, thiazetidine, thiazolidine, thiomorpholine, thiazepane,and thiazocane. The cycloalkenyl group and heterocycloalkenyl group canbe substituted or unsubstituted. The cycloalkenyl group andheterocycloalkenyl group can be substituted with one or more groupsincluding, but not limited to, optionally substituted alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylicacid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl,sulfo-oxo, or thiol, as described herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, optionally substitutedalkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” alsoincludes “heteroaryl,” which is defined as a group that contains anaromatic group that has at least one heteroatom incorporated within thering of the aromatic group. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term“non-heteroaryl,” which is also included in the term “aryl,” defines agroup that contains an aromatic group that does not contain aheteroatom. The aryl group can be substituted or unsubstituted. The arylgroup can be substituted with one or more groups including, but notlimited to, optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro,silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is aspecific type of aryl group and is included in the definition of “aryl.”Biaryl refers to two aryl groups that are bound together via a fusedring structure, as in naphthalene, or are attached via one or morecarbon-carbon bonds, as in biphenyl. Examples of aryl include, but arenot limited to, phenyl and naphtyl. Examples of heteroaryl include, butare not limited to, furanyl, pyranyl, imidazolyl, thiophenyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl,benzofuranyl, benzothiophene, indolyl, indazolyl, quinolinyl,naphthyridinyl, benzothiazolyl, benzooxazolyl, benzoimidazolyl, andbenzotriazolyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula NA¹A²A³, where A¹, A², and A³ can be, independently, hydrogen oroptionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be an optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “polyester” as usedherein is represented by the formula -(A O(O)C-A²-C(O)O)_(a)— or-(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A² can be, independently, anoptionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group described herein. The term “polyether” as used hereinis represented by the formula -(A¹O-A²O)_(a)—, where A¹ and A² can be,independently, an optionally substituted alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein and “a” is an integer of from 1 to 500. Examples of polyethergroups include polyethylene oxide, polypropylene oxide, and polybutyleneoxide.

The term “halide” as used herein refers to the halogens fluorine,chlorine, bromine, and iodine.

The term “heterocycle,” as used herein refers to single and multi-cyclicaromatic or non-aromatic ring systems in which at least one of the ringmembers is other than carbon. Heterocycle includes, but is not limitedto, pyridinde, pyrimidine, furan, thiophene, pyrrole, isoxazole,isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including,1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole,including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole,triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole,including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, triazine, including 1,2,4-triazine and1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine,piperidine, piperazine, morpholine, azetidine, tetrahydropyran,tetrahydrofuran, dioxane, and the like.

The term “hydroxyl” as used herein is represented by the formula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein.

The term “azide” as used herein is represented by the formula —N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” as used herein is represented by the formula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an optionallysubstituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.Throughout this specification “S(O)” is a short hand notation for S═O.The term “sulfonyl” is used herein to refer to the sulfo-oxo grouprepresented by the formula —S(O)₂A¹, where A¹ can be hydrogen or anoptionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “sulfone” as used herein is represented by the formulaA¹S(O)₂A², where A¹ and A² can be, independently, an optionallysubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein. The term“sulfoxide” as used herein is represented by the formula A¹S(O)A², whereA¹ and A² can be, independently, an optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedherein above. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Further, non-limiting examples include, but are not limited to, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, cycloalkynyl, heterocycloalkylyl. Organic residuescan preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4carbon atoms. In a further aspect, an organic residue can comprise 2 to18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has the structure

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have or fewer, or preferably one to sixor one to four inorganic atoms as listed above bonded together. Examplesof inorganic radicals include, but not limited to, amino, hydroxy,halogens, nitro, thiol, sulfate, phosphate, and like commonly knowninorganic radicals. The inorganic radicals do not have bonded thereinthe metallic elements of the periodic table (such as the alkali metals,alkaline earth metals, transition metals, lanthanide metals, or actinidemetals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Typically,inorganic radicals do not comprise metalloids elements such as boron,aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or thenoble gas elements, unless otherwise specifically indicated elsewhereherein.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain instances of the above defined terms may occur more than once inthe structural formulae, and upon such occurrence each term shall bedefined independently of the other.

As used herein, the term “receptor positive allosteric modulator” refersto any exogenously administered compound or agent that directly orindirectly augments the activity of the receptor in the presence or inthe absence of the endogenous ligand (such as glutamate) in an animal,in particular a mammal, for example a human. The term “receptor positiveallosteric modulator” includes a compound that is a “receptor allostericpotentiator” or a “receptor allosteric agonist,” as well as a compoundthat has mixed activity as both a “receptor allosteric potentiator” andan “mGluR receptor allosteric agonist.”

As used herein, the term “receptor allosteric potentiator” refers to anyexogenously administered compound or agent that directly or indirectlyaugments the response produced by the endogenous ligand (such asglutamate) when it binds to the orthosteric site of the receptor in ananimal, in particular a mammal, for example a human. The receptorallosteric potentiator binds to a site other than the orthosteric site(an allosteric site) and positively augments the response of thereceptor to an agonist. Because it does not induce desensitization ofthe receptor, activity of a compound as a receptor allostericpotentiator provides advantages over the use of a pure receptorallosteric agonist. Such advantages can include, for example, increasedsafety margin, higher tolerability, diminished potential for abuse, andreduced toxicity.

As used herein, the term “receptor allosteric agonist” refers to anyexogenously administered compound or agent that directly augments theactivity of the receptor in the absence of the endogenous ligand (suchas glutamate) in an animal, in particular a mammal, for example a human.The receptor allosteric agonist binds to the orthosteric glutamate siteof the receptor and directly influences the orthosteric site of thereceptor.

As used herein, the term “subject” refers to a target of administration.The subject of the herein disclosed methods can be a vertebrate, such asa mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subjectof the herein disclosed methods can be a human, non-human primate,horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.The term does not denote a particular age or sex. Thus, adult andnewborn subjects, as well as fetuses, whether male or female, areintended to be covered. A patient refers to a subject afflicted with adisease or disorder. The term “patient” includes human and veterinarysubjects.

In some aspects of the disclosed methods, the subject has been diagnosedwith a need for treatment of one or more neurological and/or psychiatricdisorder and/or any other disease state associated with glutamatedysfunction prior to the administering step. In some aspects of thedisclosed method, the subject has been diagnosed with a need forpotentiation of metabotropic glutamate receptor activity prior to theadministering step. In some aspects of the disclosed method, the subjecthas been diagnosed with a need for partial agonism of metabotropicglutamate receptor activity prior to the administering step. In someaspects, the disclosed methods can further comprise a step ofidentifying a subject having a need for treatment of a discloseddisorder.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with a disorder treatable by potentiation of mGluR4” meanshaving been subjected to a physical examination by a person of skill,for example, a physician, and found to have a condition that can bediagnosed or treated by a compound or composition that can potentiatemGluR4. As a further example, “diagnosed with a need for potentiation ofmGluR4” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditioncharacterized by mGluR4 activity. Such a diagnosis can be in referenceto a disorder, such as a disease of uncontrolled cellular proliferation,and the like, as discussed herein.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto mGluR4 activity) based upon an earlier diagnosis by a person of skilland thereafter subjected to treatment for the disorder. It iscontemplated that the identification can, in one aspect, be performed bya person different from the person making the diagnosis. It is alsocontemplated, in a further aspect, that the administration can beperformed by one who subsequently performed the administration.

As used herein, the term “diagnosed with a need for potentiation ofmetabotropic glutamate receptor activity” refers to having beensubjected to a physical examination by a person of skill, for example, aphysician, and found to have a condition that can be diagnosed ortreated by potentiation of metabotropic glutamate receptor activity.

As used herein, “diagnosed with a need for partial agonism ofmetabotropic glutamate receptor activity” means having been subjected toa physical examination by a person of skill, for example, a physician,and found to have a condition that can be diagnosed or treated bypartial agonism of metabotropic glutamate receptor activity.

As used herein, “diagnosed with a need for treatment of one or moreneurological and/or psychiatric disorder or any other disease stateassociated with glutamate dysfunction” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have one or more neurological and/or psychiatric disorderassociated with glutamate dysfunction.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, and parenteral administration, including injectable suchas intravenous administration, intra-arterial administration,intramuscular administration, and subcutaneous administration.Administration can be continuous or intermittent. In various aspects, apreparation can be administered therapeutically; that is, administeredto treat an existing disease or condition. In further various aspects, apreparation can be administered prophylactically; that is, administeredfor prevention of a disease or condition.

The term “contacting” as used herein refers to bringing a disclosedcompound and a cell, target histamine receptor, or other biologicalentity together in such a manner that the compound can affect theactivity of the target (e.g., spliceosome, cell, etc.), either directly;i.e., by interacting with the target itself, or indirectly; i.e., byinteracting with another molecule, co-factor, factor, or protein onwhich the activity of the target is dependent.

As used herein, the term “effective amount” refers to an amount that issufficient to achieve the desired result or to have an effect on anundesired condition. For example, a “therapeutically effective amount”refers to an amount that is sufficient to achieve the desiredtherapeutic result or to have an effect on undesired symptoms, but isgenerally insufficient to cause adverse side affects. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration; the route of administration; the rate of excretion ofthe specific compound employed; the duration of the treatment; drugsused in combination or coincidental with the specific compound employedand like factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of a compound at levels lowerthan those required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration. Consequently, single dose compositions cancontain such amounts or submultiples thereof to make up the daily dose.The dosage can be adjusted by the individual physician in the event ofany contraindications. Dosage can vary, and can be administered in oneor more dose administrations daily, for one or several days. Guidancecan be found in the literature for appropriate dosages for given classesof pharmaceutical products. In further various aspects, a preparationcan be administered in a “prophylactically effective amount”; that is,an amount effective for prevention of a disease or condition.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions that are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g.,compounds disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

The term “hydrolysable residue” is meant to refer to a functional groupcapable of undergoing hydrolysis, e.g., under basic or acidicconditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include sulfonate esters, including triflate, mesylate, tosylate,brosylate, and halides.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismof a biological process, or component of a process, including a protein,subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC₅₀ canrefer to the concentration of a substance that is required for 50%agonism in vivo, as further defined elsewhere herein. In a furtheraspect, EC₅₀ refers to the concentration of agonist that provokes aresponse halfway between the baseline and maximum response.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half maximal (50%) inhibitoryconcentration (IC) of a substance.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds can not be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including steps in methods of making and using thecompositions of the invention. Thus, if there are a variety ofadditional steps that can be performed it is understood that each ofthese additional steps can be performed with any specific embodiment orcombination of embodiments of the methods of the invention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

B. Compounds

In one aspect, the invention relates to compounds, or pharmaceuticallyacceptable derivatives thereof, useful as potentiators of mGluR4activity. In general, it is contemplated that each disclosed derivativecan be optionally further substituted. It is also contemplated that anyone or more derivative can be optionally omitted from the invention. Itis understood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using. It is also understood thateach variable disclosed herein is independent, one from the other,whether explicitly stated or not. For example, the phrase “R¹ and R² arephenyl or halogen” means that R¹ and R² are each independently phenyl orhalogen. Likewise, each substituent modified by k, m, n, etc. are allindependent one from the other.

1. Structure

In one aspect, the invention relates to compounds having a structurerepresented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof.

In a further aspect, the invention relates to compounds having astructure as represented above where R₁ is heteroaryl. In furtheraspects, R₁ is pyridine, pyrimidine, isothiazole, furan, thipphene,pyrazine. In a further aspect, when R₁ is pyridine, it can be optionallysubstituted with at least one fluoro, chloro and/or methoxy. In furtheraspects, when R₁ is furan, it can be optionally chloro-substituted.

In a further aspect, the invention relates to compounds having astructure as represented above where R₆ is methyl.

In a further aspect, the invention relates to compounds having astructure as represented above where R₄ is hydrogen, methyl, alkyl.

In a further aspect, the invention relates to compounds having astructure as represented above where R₇ is chloro, CF₃, alkoxy.

In a further aspect, the invention relates to compounds having astructure as represented above where R₅ and R₆ are independentlyhydrogen, alkyl, cyclohexane, methyl. In a further aspect, R₅ is ethylbenzene, tert-butyl carboxylate, acetyl, tert-butyl acetyl, furanacetyl.

In a further aspect, the invention relates to compounds having astructure as represented above where R₄ and R₅ cyclize to form asubstituted or unsubstituted 5 or 6 member ring. In a further aspect,the each atom on the ring is independently C, N, O, and S.

In a further aspect, the invention relates to compounds having astructure as represented above where R₅ and R₆ cyclize to form asubstituted or unsubstituted 5, 6, 7, or 8 member ring. In a furtheraspect, R₅ and R₆ cyclize to form a substituted or unsubstituted bicycloheptane, cyclohexane.

In further aspect, the invention relates to compounds having a structurerepresented by a formula:

In further aspect, the invention relates to compounds having a structurerepresented by a formula:

In a further aspect, the invention relates to compounds having astructure represented by a formula:

wherein R₉ is C, O, S, SO₂, SO₂—C.

A further aspect of the invention relates to compounds having astructure represented by a formula

where when R₄ is H or methyl, R₁ is not benzopyran, thienopyrazole, orthiophene.

2. Exemplary Compounds

In further aspects, a compound can have a structure represented by aformula:

The compounds disclosed herein can include all salt forms, for example,salts of both basic groups, inter alia, amines, as well as salts ofacidic groups, inter alia, carboxylic acids. The following arenon-limiting examples of anions that can form salts with protonatedbasic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate,bicarbonate, phosphate, formate, acetate, propionate, butyrate,pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate,fumarate, citrate, and the like. The following are non-limiting examplesof cations that can form salts of acidic groups: ammonium, sodium,lithium, potassium, calcium, magnesium, bismuth, lysine, and the like.

The analogs (compounds) of the present disclosure are arranged intoseveral categories to assist the formulator in applying a rationalsynthetic strategy for the preparation of analogs which are notexpressly exampled herein. The arrangement into categories does notimply increased or decreased efficacy for any of the compositions ofmatter described herein.

C. Pharmaceutical Compositions

In one aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds. That is, a pharmaceuticalcomposition can be provided comprising a therapeutically effectiveamount of at least one disclosed compound or at least one product of adisclosed method and a pharmaceutically acceptable carrier.

In certain aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptablederivatives (e.g., salt(s)) thereof) as an active ingredient, apharmaceutically acceptable carrier, and, optionally, other therapeuticingredients or adjuvants. The instant compositions include thosesuitable for oral, rectal, topical, and parenteral (includingsubcutaneous, intramuscular, and intravenous) administration, althoughthe most suitable route in any given case will depend on the particularhost, and nature and severity of the conditions for which the activeingredient is being administered. The pharmaceutical compositions can beconveniently presented in unit dosage form and prepared by any of themethods well known in the art of pharmacy.

The disclosed compounds can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), byinhalation spray, nasal, vaginal, rectal, sublingual, or topical routesof administration and can be formulated, alone or together, in suitabledosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration. In addition to the treatment ofwarm-blooded animals such as mice, rats, horses, cattle, sheep, dogs,cats, monkeys, etc., the compounds of the invention are effective foruse in humans. The term “composition” as used herein is intended toencompass a product comprising specified ingredients in predeterminedamounts or proportions, as well as any product which results, directlyor indirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. In general, pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. Accordingly, the pharmaceutical compositionsencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases oracids. When the compound of the present invention is acidic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic bases and organic bases.Salts derived from such inorganic bases include aluminum, ammonium,calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium,manganese (-ic and -ous), potassium, sodium, zinc and the like salts.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acids”includes inorganic acids, organic acids, and salts prepared therefrom,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, and/or pharmaceutically acceptable salt(s) thereof, can alsobe administered by controlled release means and/or delivery devices. Thecompositions can be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention can include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the compounds of the invention. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds. The pharmaceutical carrieremployed can be, for example, a solid, liquid, or gas. Examples of solidcarriers include lactose, terra alba, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, and stearic acid. Examples of liquidcarriers are sugar syrup, peanut oil, olive oil, and water. Examples ofgaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention can comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

A potentiated amount of an mGluR agonist to be administered incombination with an effective amount of a disclosed compound is expectedto vary from about 0.1 milligram per kilogram of body weight per day(mg/kg/day) to about 100 mg/kg/day and is expected to be less than theamount that is required to provide the same effect when administeredwithout an effective amount of a disclosed compound. Preferred amountsof a co-administered mGluR agonist are able to be determined by oneskilled in the art.

In the treatment of conditions which require potentiation ofmetabotropic glutamate receptor activity, an appropriate dosage levelwill generally be about 0.01 to 500 mg per kg patient body weight perday which can be administered in single or multiple doses. Preferably,the dosage level will be about 0.1 to about 250 mg/kg per day; morepreferably about 0.5 to about 100 mg/kg per day. A suitable dosage levelcan be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day,or about 0.1 to 50 mg/kg per day. Within this range the dosage can be0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500,600, 750, 800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds can be administered on a regimen of 1 to 4 times per day,preferably once or twice per day. This dosage regimen can be adjusted toprovide the optimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The disclosed pharmaceutical compositions can further comprise othertherapeutically active compounds, as discussed further herein, which areusually applied in the treatment of the above mentioned pathologicalconditions.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

In a further aspect, a pharmaceutical composition can comprise atherapeutically effective amount of any one or more disclosed compoundand a pharmaceutically acceptable carrier. In a further aspect, apharmaceutical composition can comprise a therapeutically effectiveamount of one or more product of any disclosed method and apharmaceutically acceptable carrier. In one aspect, the inventionrelates to a method for manufacturing a medicament comprising combiningat least one disclosed compound or at least one product of a disclosedmethod with a pharmaceutically acceptable carrier or diluent.

Accordingly, the pharmaceutical compositions of the present inventioninclude those that contain one or more other active ingredients, inaddition to a compound of the present invention.

The above combinations include combinations of a disclosed compound notonly with one other active compound, but also with two or more otheractive compounds. Likewise, disclosed compounds may be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of the diseases orconditions for which disclosed compounds are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the present invention to the secondactive ingredient can be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element can be prior to, concurrentto, or subsequent to the administration of other agent(s).

Accordingly, the subject compounds can be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the disclosed compounds. The subject compound andthe other agent may be coadministered, either in concomitant therapy orin a fixed combination.

In one aspect, the compound can be employed in combination withanti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's (non-sterodialanti-inflammatory drugs) including ibuprofen, vitamin E, andanti-amyloid antibodies. In a further aspect, the subject compound maybe employed in combination with sedatives, hypnotics, anxiolytics,antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine,aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capuride, carbocloral, chloralbetaine, chloral hydrate, clomipramine, clonazepam, cloperidone,clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine,cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone,divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol,etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine,flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam,maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam,nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine,pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital,prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine,reclazepam, risperidone, roletamide, secobarbital, sertraline,suproclone, temazepam, thioridazine, thiothixene, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, ziprasidone, zolazepam, Zolpidem, and saltsthereof, and combinations thereof, and the like, or the subject compoundmay be administered in conjunction with the use of physical methods suchas with light therapy or electrical stimulation.

In a further aspect, the compound can be employed in combination withlevodopa (with or without a selective extracerebral decarboxylaseinhibitor such as carbidopa or benserazide), anticholinergics such asbiperiden (optionally as its hydrochloride or lactate salt) andtrihexyphenidyl (benzhexyl)hydrochloride, COMT inhibitors such asentacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptorantagonists, cholinergic agonists, NMDA receptor antagonists, serotoninreceptor antagonists and dopamine receptor agonists such as alentemol,bromocriptine, fenoldopam, lisuride, naxagolide, pergolide andpramipexole. It will be appreciated that the dopamine agonist may be inthe form of a pharmaceutically acceptable salt, for example, alentemolhydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolidehydrochloride and pergolide mesylate. Lisuride and pramipexol arecommonly used in a non-salt form.

In a further aspect, the compound can be employed in combination with acompound from the phenothiazine, thioxanthene, heterocyclicdibenzazepine, butyrophenone, diphenylbutylpiperidine and indoloneclasses of neuroleptic agent. Suitable examples of phenothiazinesinclude chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine. Suitable examples ofthioxanthenes include chlorprothixene and thiothixene. An example of adibenzazepine is clozapine. An example of a butyrophenone ishaloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisulpride, benzhexyl, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

In one aspect, the compound can be employed in combination with ananti-depressant or anti-anxiety agent, including norepinephrine reuptakeinhibitors (including tertiary amine tricyclics and secondary aminetricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamineoxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase(RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs),corticotropin releasing factor (CRF) antagonists, α-adrenoreceptorantagonists, neurokinin-1 receptor antagonists, atypicalanti-depressants, benzodiazepines, 5-HTJA agonists or antagonists,especially 5-HT1A partial agonists, and corticotropin releasing factor(CRF) antagonists. Specific agents include: amitriptyline, clomipramine,doxepin, imipramine and trimipramine; amoxapine, desipramine,maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine,paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromineand selegiline; moclobemide: venlafaxine; duloxetine; aprepitant;bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam,chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam,lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone andipsapirone, and pharmaceutically acceptable salts thereof.

In the treatment of conditions which require potentiation of mGluR4activity an appropriate dosage level will generally be about 0.01 to 500mg per kg patient body weight per day which can be administered insingle or multiple doses. Preferably, the dosage level will be about 0.1to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kgper day. A suitable dosage level may be about 0.01 to 250 mg/kg per day,about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day.Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50mg/kg per day. For oral administration, the compositions are preferablyprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10, 15. 20, 25, 50, 75, 100,150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The compounds may be administered on aregimen of 1 to 4 times per day, preferably once or twice per day. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse. It will be understood, however, that the specific dose leveland frequency of dosage for any particular patient may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

In one aspect, the invention relates to pharmaceutical compositionscomprising a compound having a structure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof; and a pharmaceutically acceptablecarrier.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising a compound having a structure as representedabove where R₁ is heteroaryl, or a pharmaceutically acceptable saltthereof or a pharmaceutically acceptable derivative thereof; and apharmaceutically acceptable carrier. In further aspects, R₁ is pyridine,pyrimidine, isothiazole, furan, thipphene, pyrazine. In a furtheraspect, when R₁ is pyridine, it can be optionally substituted with atleast one fluoro, chloro and/or methoxy. In further aspects, when R₁ isfuran, it can be optionally chloro-substituted.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising a compound having a structure as representedabove where R₆ is methyl, or a pharmaceutically acceptable salt thereofor a pharmaceutically acceptable derivative thereof; and apharmaceutically acceptable carrier.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising a compound having a structure as representedabove where R₄ is hydrogen, methyl, alkyl, or a pharmaceuticallyacceptable salt thereof or a pharmaceutically acceptable derivativethereof; and a pharmaceutically acceptable carrier.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising a compound having a structure as representedabove where R₇ is chloro, CF₃, alkoxy, or a pharmaceutically acceptablesalt thereof or a pharmaceutically acceptable derivative thereof; and apharmaceutically acceptable carrier.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising a compound having a structure as representedabove where R₅ and R₆ are independently hydrogen, alkyl, cyclohexane,methyl, or a pharmaceutically acceptable salt thereof or apharmaceutically acceptable derivative thereof; and a pharmaceuticallyacceptable carrier. In a further aspect, R₅ is ethyl benzene, tert-butylcarboxylate, acetyl, tert-butyl acetyl, furan acetyl.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising a compound having a structure as representedabove where R₄ and R₅ cyclize to form a substituted or unsubstituted 5or 6 member ring, or a pharmaceutically acceptable salt thereof or apharmaceutically acceptable derivative thereof; and a pharmaceuticallyacceptable carrier. In a further aspect, the each atom on the ring isindependently C, N, O, and S.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising a compound having a structure as representedabove where R₅ and R₆ cyclize to form a substituted or unsubstituted 5,6, 7, or 8 member ring, or a pharmaceutically acceptable salt thereof ora pharmaceutically acceptable derivative thereof; and a pharmaceuticallyacceptable carrier. In a further aspect, R₅ and R₆ cyclize to form asubstituted or unsubstituted bicyclo heptane, cyclohexane.

In further aspect, the invention relates to pharmaceutical compositionscomprising a compound having a structure represented by a formula:

or a pharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof; and a pharmaceutically acceptablecarrier.

In further aspect, the invention relates to pharmaceutical compositionscomprising a compound having a structure represented by a formula:

or a pharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof; and a pharmaceutically acceptablecarrier.

In further aspect, the invention relates to pharmaceutical compositionscomprising a compound having a structure represented by a formula:

wherein R₈ is C, O, S, SO₂, SO₂—C, or a pharmaceutically acceptable saltthereof or a pharmaceutically acceptable derivative thereof; and apharmaceutically acceptable carrier.

D. Methods of Using Compounds, Products and Compositions

mGluR4 belongs to the group III mGluR subfamily and is located inpredominantly presynaptic locations in the central nervous system whereit is functions as an auto- and heteroreceptor to regulate the releaseof both GABA and glutamate. In addition, mGluR4 is also expressed at alow level in some postsynaptic locations. mGluR4 is expressed in mostbrain regions, particularly in neurons known to play key roles in thefollowing functions of the CNS:

-   -   a) learning and memory;    -   b) regulation of voluntary movement and other motor functions    -   c) motor learning    -   d) emotional responses    -   e) habit formation, including repetitive tasks and preservative        thought processes    -   f) reward systems    -   g) vision and olfaction    -   h) cerebellar functions;    -   i) feeding and the regulation of hypothalamic hormones; and    -   j) sleep and wakefulness.        As such, mGluR4 plays a major role in the modulation of        CNS-related diseases, syndromes and non-CNS related diseases or        conditions the like, for example,    -   a) Parkinson's disease, parkinsonism, and other disorders        involving akinesia or bradykinesia    -   b) Dystonia    -   c) Huntington's diseases and other disorders involving        involuntary movements and dyskinesias    -   d) Tourette's syndrome and related ticking disorders    -   e) Obsessive/compulsive disorder and other preservative        behavioral disorders    -   f) Addictive disorders (including drug abuse, eating disorders,        and)    -   g) Schizophrenia and other psychotic disorders    -   h) Posttraumatic stress disorder    -   i) Anxiety disorders;    -   c) motor effects after alcohol consumption or other drug-induced        motor disorders;    -   d) neurogenic fate commitment and neuronal survival;    -   e) epilepsy;    -   f) certain cancers, for example, medulloblastoma;    -   g) type 2 diabetes, and/or other metabolic disorders; and    -   h) taste enhancement/blockade.

The disclosed compounds can act as potentiators of the metabotropicglutamate receptor activity (mGluR4). Therefore, in one aspect, thedisclosed compounds can be used to treat one or more mGluR4 associateddisorders that result in dysfunction in a mammal.

The disclosed compounds can be used as single agents or in combinationwith one or more other drugs in the treatment, prevention, control,amelioration or reduction of risk of the aforementioned diseases,disorders and conditions for which compounds of formula I or the otherdrugs have utility, where the combination of drugs together are safer ormore effective than either drug alone. The other drug(s) can beadministered by a route and in an amount commonly used therefore,contemporaneously or sequentially with a disclosed compound. When adisclosed compound is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchdrugs and the disclosed compound is preferred. However, the combinationtherapy can also be administered on overlapping schedules. It is alsoenvisioned that the combination of one or more active ingredients and adisclosed compound will be more efficacious than either as a singleagent.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with glutamatedysfunction. Thus, provided is a method of treating or preventing adisorder in a subject comprising the step of administering to thesubject at least one disclosed compound; at least one disclosedpharmaceutical composition; and/or at least one disclosed product in adosage and amount effective to treat the disorder in the subject.

Also provided is a method for the treatment of one or more neurologicaland/or psychiatric disorders associated with glutamate dysfunction in asubject comprising the step of administering to the subject at least onedisclosed compound; at least one disclosed pharmaceutical composition;and/or at least one disclosed product in a dosage and amount effectiveto treat the disorder in the subject.

Examples of disorders associated with glutamate dysfunction include:acute and chronic neurological and psychiatric disorders such ascerebral deficits subsequent to cardiac bypass surgery and grafting,stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia(including AIDS-induced dementia), Alzheimer's disease, Huntington'sChorea, amyotrophic lateral sclerosis, multiple sclerosis, oculardamage, retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine(including migraine headache), urinary incontinence, substancetolerance, addictive behavior, including addiction to substances(including opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal fromsuch addictive substances (including substances such as opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.), obesity, psychosis, schizophrenia, anxiety(including generalized anxiety disorder, panic disorder, and obsessivecompulsive disorder), mood disorders (including depression, mania,bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus,macular degeneration of the eye, emesis, brain edema, pain (includingacute and chronic pain states, severe pain, intractable pain,neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleepdisorders (including narcolepsy), attention deficit/hyperactivitydisorder, conduct disorder, diabetes and other metabolic disorders,taste alteration, and cancer.

Anxiety disorders that can be treated or prevented by the compositionsdisclosed herein include generalized anxiety disorder, panic disorder,and obsessive compulsive disorder. Addictive behaviors include addictionto substances (including opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal fromsuch addictive substances (including substances such as opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.) and substance tolerance.

Thus, in some aspects of the disclosed method, the disorder is dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, psychoticdepression.

Also provided is a method for treating or prevention anxiety,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding anxiety and related disorders. These include: panic disorderwith or without agoraphobia, agoraphobia without history of panicdisorder, specific phobia, social phobia, obsessive-compulsive disorder,post-traumatic stress disorder, acute stress disorder, generalizedanxiety disorder, anxiety disorder due to a general medical condition,substance-induced anxiety disorder and anxiety disorder not otherwisespecified.

In one aspect, the invention relates to methods for the treatment of aneurotransmission dysfunction and other disease states associated withmGluR4 activity in a mammal comprising the step of administering to themammal at least one compound in a dosage and amount effective to treatthe dysfunction in the mammal, the compound having a structurerepresented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof. In various aspects, the dysfunction isone or more of Parkinson's disease, schizophrenia, psychosis,“schizophrenia-spectrum” disorder, depression, bipolar disorder,cognitive disorder, delirium, amnestic disorder, anxiety disorder,attention disorder, obesity, eating disorder, or NMDA receptor-relateddisorder. In various further aspects, the dysfunction is one or more ofParkinson's disease; anxiety; motor effects after alcohol consumption;neurogenic fate commitment and neuronal survival; epilepsy; or certaincancers, for example, medulloblastoma.

2. Potentiating mGluR4 Activity in Subjects

In a further aspect, the invention relates to methods for potentiatingmGluR4 activity in a subject comprising the step of administering to thesubject at least one compound in a dosage and amount effective topotentiate mGluR4 activity in the subject, the compound having astructure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof, in a dosage and amount effective topotentiate mGluR4 receptor activity in the subject.

In one aspect, the invention relates to methods of potentiating mGluR4activity in at least one cell comprising the step of contacting the atleast one cell with at least one compound having a structure representedby a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof, in an amount effective to potentiatemGluR4 receptor activity in the at least one cell.

In certain aspects, a subject, for example a mammal or a human, has beendiagnosed with the dysfunction prior to the administering step. Infurther aspects, a disclosed method can further comprise the step ofidentifying a subject, for example a mammal or a human, having a needfor treatment of a dysfunction. In further aspects, a subject, forexample a mammal or a human, has been diagnosed with a need forpotentiation of mGluR4 receptor activity prior to the administeringstep. In further aspects, a disclosed method can further comprise thestep of identifying a subject, for example a mammal or a human, having aneed for potentiation of mGluR4 receptor activity. In further aspects, acell (e.g., a mammalian cell or a human cell) has been isolated from asubject, for example a mammal or a human, prior to the contacting step.In further aspects, contacting is via administration to a subject, forexample a mammal or a human.

In one aspect, the invention relates to methods for potentiating mGluR4activity in at least one cell comprising the step of contacting the atleast one cell with at least one disclosed compound in an amounteffective to potentiate mGluR4 receptor activity in the at least onecell.

In one aspect, the invention relates to methods for potentiating mGluR4activity in a subject comprising the step of administering to thesubject a therapeutically effective amount of at least one disclosedcompound in a dosage and amount effective to potentiate mGluR4 receptoractivity in the subject.

In one aspect, the invention relates to methods for the treatment of adisorder associated with mGluR4 neurotransmission dysfunction or otherdisease state in a mammal comprising the step of administering to themammal at least one disclosed compound in a dosage and amount effectiveto treat the disorder in the mammal.

The disclosed compounds can be used to treat a wide range ofneurological and psychiatric disorders and other disease statesassociated with glutamate dysfunction. Non-limiting examples of thesediseases includes movement disorders, including akinesias andakinetic-rigid syndromes (including Parkinson's disease), dystonia,epilepsy, chorea, neurogenerative diseases such as dementia,Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer'sdisease, Pick's disease, Creutzfeldt-Jakob disease, pain, migraines,diabetes, obesity and eating disorders, sleep disorders includingnarcolepsy, and anxiety or affective disorders, including generalizedanxiety disorder, panic attacks, unipolar depression, bipolar disorder,psychotic depression, and related disorders, cognitive disordersincluding dementia (associated with Alzheimer's disease, ischemia,trauma, stroke, HIV disease, Parkinson's disease, Huntington's diseaseand other general medical conditions or substance abuse), delirium,amnestic disorders, age-related cognitive decline, schizophrenia orpsychosis including schizophrenia (paranoid, disorganized, catatonic orundifferentiated), schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, cancer and inflammation (including MS). Of the disordersabove, the treatment of Parkinson's disease, movement disorders,cognitive disorders, neurodegenerative diseases, obesity and pain are ofparticular importance.

In one aspect, the disclosed compounds can be used to treat, or can be acomponent of a pharmaceutical composition used to treat movementdisorders. As such, disclosed herein in a method for treating a movementdisorder, comprising the step of administering to a mammal in need oftreatment at least one compound in a dosage and amount effective totreat the disorder in the mammal, wherein the disorder is selected fromParkinson's disease, Huntington's disease, dystonia, Wilson's disease,chorea, ataxia, ballism, akathesia, athetosis, bradykinesia, ridigity,postural instability, inherited ataxias such as Friedreich's ataxia,Machado-Joseph disease, spinocerebellar ataxias, Tourette syndrome andother tic disorders, essential tremor, cerebral palsy, stroke,encephalopathies, and intoxication.

In a further aspect, the disclosed compounds can be used to treat, orcan be a component of a pharmaceutical composition used to treatcognitive disorders. As such, disclosed herein in a method for treatinga cognitive disorder, comprising the step of administering to a mammalin need of treatment at least one compound in a dosage and amounteffective to treat the disorder in the mammal, wherein the disorder isselected from dementia (associated with Alzheimer's disease, ischemia,trauma, stroke, HIV disease, Parkinson's disease, Huntington's diseaseand other general medical conditions or substance abuse), delirium,amnestic disorders and age-related cognitive decline. The fourth edition(Revised) of the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV-TR) (2000, American Psychiatric Association, Washington D.C.)provides a diagnostic tool for cognitive disorders including dementia(associated with Alzheimer's disease, ischemia, trauma, stroke, HIVdisease, Parkinson's disease, Huntington's disease and other generalmedical conditions or substance abuse), delirium, amnestic disorders andage-related cognitive decline.

In a further aspect, the disclosed compounds can be used to treat, orcan be a component of a pharmaceutical composition used toneurodegenerative disorders. As such, disclosed herein in a method fortreating a neurodegenerative disorder, comprising the step ofadministering to a mammal in need of treatment at least one compound ina dosage and amount effective to treat a neurodegenerative disorder inthe mammal.

In a still further aspect, the disclosed compounds provide a method fortreating schizophrenia or psychosis. As such, disclosed herein in amethod for treating a disorder related to schizophrenia or psychosis,comprising the step of administering to a mammal in need of treatment atleast one compound in a dosage and amount effective to treat thedisorder in the mammal, wherein the disorder related to schizophrenia orpsychosis is selected from paranoid, disorganized, catatonic orundifferentiated, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-inducedpsychotic disorder. The fourth edition (Revised) of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR) (2000, AmericanPsychiatric Association, Washington D.C.) provides a diagnostic tool forc include paranoid, disorganized, catatonic or undifferentiated,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, substance-induced psychoticdisorder.

The subject compounds are further useful in the prevention, treatment,control, amelioration or reduction of risk of the aforementioneddiseases, disorders and conditions in combination with other agents,including an mGluR agonist.

3. Potentiation of mGluR4 Response

In one aspect, the compound exhibits potentiation of mGluR4 response toglutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with rat mGluR4 inthe presence of the compound, compared to the response to glutamate inthe absence of the compound, compared to the response to glutamate inthe absence of the compound, having an EC₅₀ of less than about 1.0×10⁻⁵,for example, less than about 5.0×10⁻⁵, less than about 1.0×10⁻⁶, lessthan about 5.0×10⁻⁷, less than about 1.0×10⁻⁷, less than about5.0×10^(-s), or less than about 1.0×10⁻⁸.

4. Coadministration Methods

The disclosed compounds may be used as single agents or in combinationwith one or more other drugs in the treatment, prevention, control,amelioration or reduction of risk of the aforementioned diseases,disorders and conditions for which compounds of formula I or the otherdrugs have utility, where the combination of drugs together are safer ormore effective than either drug alone. The other drug(s) may beadministered by a route and in an amount commonly used therefore,contemporaneously or sequentially with a disclosed compound. When adisclosed compound is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchdrugs and the compound is preferred. However, the combination therapycan also be administered on overlapping schedules. It is also envisionedthat the combination of one or more active ingredients and a disclosedcompound can be more efficacious than either as a single agent.

In one aspect, the compounds can be coadministered with anti-Alzheimer'sagents, beta-secretase inhibitors, gamma-secretase inhibitors,muscarinic agonists, muscarinic potentiators HMG-CoA reductaseinhibitors, NSAIDs and anti-amyloid antibodies. In a further aspect, thecompounds can be administered in combination with sedatives, hypnotics,anxiolytics, antipsychotics, selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyT1inhibitors and the like such as, but not limited to: risperidone,clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium,phenobarbitol, and salts thereof and combinations thereof.

In a further aspect, the subject compound may be used in combinationwith levodopa (with or without a selective extracerebral decarboxylaseinhibitor), anitcholinergics such as biperiden, COMT inhibitors such asentacapone, A2a adenosine antagonists, cholinergic agonists, NMDAreceptor antagonists and dopamine agonists.

In one aspect, the invention relates to methods for the treatment of aneurotransmission dysfunction and other disease states associated withmGluR4 activity in a mammal comprising the step of co-administering tothe mammal at least one compound in a dosage and amount effective totreat the dysfunction in the mammal, the compound having a structurerepresented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof with a drug having a known side-effect ofincreasing metabotropic glutamate receptor activity.

In one aspect, the invention relates to methods for the treatment of aneurotransmission dysfunction and other disease states associated withmGluR4 activity in a mammal comprising the step of co-administering tothe mammal at least one compound in a dosage and amount effective totreat the dysfunction in the mammal, the compound having a structurerepresented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof with a drug known to treat a disorderassociated with increasing metabotropic glutamate receptor activity.

In one aspect, the invention relates to methods for the treatment of aneurotransmission dysfunction and other disease states associated withmGluR4 activity in a mammal comprising the step of co-administering tothe mammal at least one compound in a dosage and amount effective totreat the dysfunction in the mammal, the compound having a structurerepresented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof with a drug known to treat theneurotransmission dysfunction and other disease states.

E. Metabotropic Glutamate Receptor Activity

The disclosed compounds and compositions can be evaluated for theirability to act as a potentiator of metabotropic glutamate receptoractivity, in particular mGluR4 activity, by any suitable knownmethodology known in the art. For example, Chinese Hamster Ovary (CHO)cells transfected with human mGluR4 or HEK cells co-transfected with ratmGluR4 and the G-protein regulated Inwardly Rectifying Potassium channel(GIRK) were plated in clear bottom assay plates for assay in a HamamatsuFDSS Fluorometric Plate Reader. The cells were loaded with either aCa2+-sensitive fluorescent dye or the thallium responsive dye and theplates were washed and placed into a suitable kinetic plate reader. Forhuman mGluR4 assays, a fluorescence baseline was established for 3-5seconds, the disclosed compounds were then added to the cells, and theresponse in cells was measured. Approximately two and a half minuteslater, a concentration of mGluR4 orthosteric agonist (e.g. glutamate orL-AP4) eliciting approximately 20% (EC20) of the maximal agonistresponse was added to the cells, and the response was measured. Twominutes later, a concentration of mGluR4 agonist (e.g. glutamate orL-AP4) eliciting 80% (EC80) of the maximal agonist response was added tothe cells, and the response was measured. For rat mGluR4/GIRKexperiments, a baseline was established for approximately five seconds,disclosed compounds were added, and either an EC20 or EC80 concentrationof agonist was added approximately two and one half minutes later.Potentiation of the agonist response of mGluR4 by the disclosedcompounds was observed as an increase in response to the EC20concentration of agonist in the presence of compound compared to theresponse to agonist in the absence of compound. Similarly, antagonism ofthe agonist response of mGluR4 by the disclosed compounds was observedas a decrease in response to the EC80 concentration of agonist in thepresence of compound compared to the response to agonist in the absenceof compound.

The above described assay operated in two modes. In the first mode, arange of concentrations of the disclosed compounds are added to cells,followed by a single fixed concentration of agonist. If the compoundacts as a potentiatior, an EC₅₀ value for potentiation and a maximumextent of potentiation by the compound at this concentration of agonistis determined by non-linear curve fitting. If the compound acts as anoncompetitive antagonist, an IC₅₀ value is determined by non-linearcurve fitting. In the second mode, several fixed concentrations of thedisclosed compounds are added to various wells on a plate, followed by arange in concentrations of agonist for each concentration of disclosedcompound. The EC₅₀ values for the agonist at each concentration ofcompound are determined by non-linear curve fitting. A decrease in theEC₅₀ value of the agonist with increasing concentrations of the samplecompound (a leftward shift of the agonist concentration-response curve)is an indication of the degree of mGluR4 potentiation at a givenconcentration of the sample compound. A decrease in the maximal responseof the agonist with increasing concentrations of the sample compounds,with or without a rightward shift in agonist potency, is an indicationof the degree of noncompetitive antagonism at mGluR4. The second modealso indicates whether the sample compounds also affect the maximumresponse to mGluR4 to agonists.

In particular, the compounds of the disclosed examples were found tohave activity in potentiating the mGluR4 receptor in the aforementionedassays, generally with an EC₅₀ for potentiation of less than about 10μM. One aspect of the disclosed compounds have activity in potentiatingrat and human mGluR4 receptors with an EC₅₀ for potentiation of lessthan about 500 nM. These compounds further caused a leftward shift ofthe agonist EC₅₀ by greater than 3-fold. These compounds can be positiveallosteric modulators (potentiators) of human and rat mGluR4 and wereselective for mGluR4 compared to the other seven subtypes ofmetabotropic glutamate receptors.

F. Manufacture of a Medicament

In one aspect, the invention relates to methods for the manufacture of amedicament for potentiating mGluR4 receptor activity in a mammalcomprising combining a compound having a structure represented by aformula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof with a pharmaceutically acceptablecarrier.

Thus, the disclosed compounds and compositions can be further directedto a method for the manufacture of a medicament for potentiatingglutamate receptor activity (e.g., treatment of one or more neurologicaland/or psychiatric disorder and other disease states associated withglutamate dysfunction) in mammals (e.g., humans) comprising combiningone or more disclosed compounds, products, or compositions with apharmaceutically acceptable carrier or diluent.

G. Uses of Compounds

In one aspect, the invention relates to uses of a compound forpotentiating mGluR4 receptor activity in a mammal, wherein the compoundhas a structure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof.

The disclosed uses for potentiating mGluR4 receptor activity in a mammalcan further be directed for use in treating one or more disorders, forexample neurological and psychiatric disorders and other disease statesassociated with glutamate dysfunction (e.g., Parkinson's disease) in asubject, for example a mammal or a human.

H. Kits

In one aspect, the invention relates to kits comprising a compoundhaving a structure represented by a formula:

wherein W, X, Y and Z are independently CH, N or CR₃; wherein A isselected from O or S; wherein R₁ is selected from heteroaryl optionallysubstituted with one or more R₈, aryl, or a ring such as a C₃₋₈ memberedring containing C, O, S or N, optionally substituted with one or moreR₈; wherein R₂ is selected from: H, halogen, CF₃, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl; wherein R₃ is selected from: H, halogen, CF₃, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl; wherein R₂ may be combined with R₃ to form carbonyl,thiocarbonyl, or a ring such as a C₃₋₈ membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₄ is selectedfrom H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₇; wherein R₄ and R₅ may cyclize to form aC₃₋₈ membered ring containing C, O, S or N, optionally substituted withone or more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a C₃₋₇ member ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈. R₅ and R₆ may cyclize toform a C₃₋₇ member ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl, aryl, heteroaryl, CONR₁R₂, CN orCF₃; and wherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, CN, CONR₁R₂, SO2NR₁R₂, OC₁₋₆ alkyl, CF₃, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable derivative thereof, and one or more of a drug having a knownside-effect of increasing metabotropic glutamate receptor activity, adrug known to treat a disorder associated with increasing metabotropicglutamate receptor activity, and/or a drug known to treat theneurotransmission dysfunction and other disease states.

In various aspects, the kits can comprise disclosed compounds,compositions, and/or products co-packaged, co-formulated, and/orco-delivered with other components. For example, a drug manufacturer, adrug reseller, a physician, or a pharmacist can provide a kit comprisinga disclosed oral dosage forms and another component for delivery to apatient.

In further aspects, the kits can comprise one or more other components(e.g., one or more of a drug having a known side-effect of increasingmetabotropic glutamate receptor activity, a drug known to treat adisorder associated with increasing metabotropic glutamate receptoractivity, and/or a drug known to treat the neurotransmission dysfunctionand other disease states) and instructions for coadministration to apatient with one or more disclosed compounds, compositions, and/orproducts. For example, a drug manufacturer, a drug reseller, aphysician, or a pharmacist can provide a kit comprising one or moreother components (e.g., one or more of a drug having a known side-effectof increasing metabotropic glutamate receptor activity, a drug known totreat a disorder associated with increasing metabotropic glutamatereceptor activity, and/or a drug known to treat the neurotransmissiondysfunction and other disease states) and instructions forcoadministration to a patient with one or more disclosed compounds,compositions, and/or products.

I. EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of disclosed herein areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.All reactions were carried out under an argon atmosphere employingstandard chemical techniques. Solvents for extraction, washing andchromatography were HPLC grade. All reagents were purchased from AldrichChemical Co. at the highest commercial quality and were used withoutpurification. Microwave-assisted reactions were conducted using aBiotage Initiator-60. All NMR spectra were recorded on a 400 MHz BrukerAMX NMR. ¹H chemical shifts are reported in δ values in ppm downfieldfrom TMS as the internal standard in DMSO. Data are reported as follows:chemical shift, multiplicity (s=singlet, d=doublet, t=triplet,q=quartet, br=broad, m=multiplet), integration, coupling constant (Hz).¹³C chemical shifts are reported in δ values in ppm with the DMSO carbonpeak set to 39.5 ppm. Low resolution mass spectra were obtained on anAgilent 1200 LCMS with electrospray ionization. High resolution massspectra were recorded on a Waters QToF-API-US plus Acquity system withelectrospray ionization. Analytical thin layer chromatography wasperformed on 250 M silica gel 60 F₂₅₄ plates. Merck silica gel (60,particle size 0.040-0.063 mm) was used for flash column chromatography.Analytical HPLC was performed on an Agilent 1200 analytical LCMS with UVdetection at 214 nm and 254 nm along with ELSD detection. Preparativepurification of library compounds was performed on a custom Agilent 1200preparative LCMS with collection triggered by mass detection. All yieldsrefer to analytically pure and fully characterized materials (¹H NMR,¹³C NMR analytical LCMS and Hi-Res MS).

The following is a summary of exemplified compounds below. As statedabove, the examples represent aspects of the present invention and arenot intended to be limiting thereof:

-   Example 1.3.1:    N-(4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)-3-methoxyphenyl)picolinamide-   Example 1.3.2:    N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)picolinamide-   Example 1.3.3:    N-(4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)picolinamide-   Example 1.3.4:    N-(3-Chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-6-fluoropicolinamide    (TFA)-   Example 1.3.5:    N-(3-Chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)thiazole-4-carboxamide    (TFA)-   Example 1.3.6:    N-(3-Chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)pyrimidine-4-carboxamide-   Example 1.3.7:    N-(3-Chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-3-fluoropicolinamide    (TFA)-   Example 1.3.8:    5-Chloro-N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)furan-2-carboxamide-   Example 1.3.9:    N-(3-chloro-4-(1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H,5H,6H,7H,7aH)-yl)phenyl)picolinamide-   Example 1.3.10:    N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)phenyl)picolinamide-   Example 1.3.11:    N-(3-chloro-4-(3-methyl-2,5-dioxoimidazolin-1-yl)phenyl)picolinamide-   Example 1.3.12:    N-(3-chloro-4-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)phenyl)picolinamide-   Example 1.3.13:    N-(3-chloro-4-(2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)phenyl)picolinamide-   Example 1.3.14:    N-(3-chloro-4-(6,8-dioxo-5,7-diazaspiro[3.4]octan-7-yl)phenyl)picolinamide-   Example 1.3.15:    N-(3-chloro-4-(2,4-dioxo-1,3-diazaspiro[4.6]undecan-3-yl)phenyl)picolinamide-   Example 1.3.16:    (S)-N-(3-chloro-4-(4-isopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide-   Example 1.3.17:    (R)—N-(3-chloro-4-(4-isopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide-   Example 1.3.18:    N-(3-chloro-4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide-   Example 1.3.19:    (R)—N-(4-(4-Benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamide-   Example 1.3.20:    (S)-N-(4-(4-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamide-   Example 1.3.21:    N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide-   Example 1.3.22:    N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-3-fluoropicolinamide    (TFA)-   Example 1.3.23:    6-Chloro-N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide    (TFA)-   Example 1.3.24:    N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)thiophene-2-carboxamide-   Example 1.3.25:    N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiazole-2-carboxamide    (TFA)-   Example 1.3.26:    N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiazole-4-carboxamide    (TFA)-   Example 1.3.27:    N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-3,5-difluoropicolinamide    (TFA)-   Example 1.3.28:    5-Chloro-N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)furan-2-carboxamide-   Example 1.3.29:    N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-6-fluoropicolinamide    (TFA)-   Example 1.3.30:    N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)picolinamide-   Example 1.3.31:    N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)pyrazine-2-carboxamide-   Example 1.3.32: 6-Chloro    N-(3-chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,    8H, 8aH)-yl)phenyl)picolinamide-   Example 1.3.33:    N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)thiophene-2-carboxamide-   Example 1.3.34:    N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)thiazole-2-carboxamide-   Example 1.3.35:    N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)thiazole-4-carboxamide-   Example 1.3.36:    N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)-3,5-difluoropicolinamide-   Example 1.3.37:    5-Chloro-N-(3-chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,    8H,8aH)-yl)phenyl)-furan-2-carboxamide-   Example 1.3.38:    N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)-6-fluoropicolinamide-   Example 1.3.39:    N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,    8aH)-yl)phenyl)-3-fluoropicolinamide-   Example 1.3.40:    N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,    8aH)-yl)phenyl)picolinamide-   Example 1.3.41:    N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]dioxothiazin-2(3H,8H,    8aH)-yl)phenyl)picolinamide-   Example 1.3.42:    N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,    8aH)-yl)phenyl)-6-fluoropicolinamide-   Example 1.3.43:    N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,    8aH)-yl)phenyl)thiazole-4-carboxamide-   Example 1.3.44:    tert-butyl-2-(2-chloro-4-(picolinamide)phenyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate-   Example 1.3.45:    N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-phenyl)picolinamide-   Example 1.3.46:    N-(3-chloro-4-(7-methyl-1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-yl)phenyl)picolinamide-   Example 1.3.47 :    N-(3-chloro-4-(7-(methylsulfonyl)-1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-yl)phenyl)picolinamide

Example 1.1-1.3

The compounds claimed in this invention can be prepared according to thefollowing general procedure methods.

Examples of cyclic amides of type 1.3 can be prepared as outlined inScheme 1. Starting from the appropriately substituted amino acids (oramino esters), cyclization with isocyanates (or isothiocyanates) underbasic conditions provides intermediate of type 1.1. Reduction of thenitroarene yields the anilines (1.2) followed by acylation givesExamples 1.3.

Example 1.3.1N-(4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)-3-methoxyphenyl)picolinamide

Procedure A:

Step 1: A mixture of pipecolinic acid (500 mg; 3.87 mmol),2-methoxy-4-nitrophenylisocyanate (902 mg; 4.65 mmol) and 9:1 THF:2 MNaOH were reacted in a microwave vessel at 160° C. for 10 min. Thereaction mixture was then cooled to rt and purified by columnchromatography (1:1, EtOAc:hexanes) to afford 736 mg of2-(2-methoxy-4-nitrophenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione,1.1.1, (62%).

LCMS: >98% @254 nm, R_(T)=2.60 min., m/z=306.2 [M+H]⁺

Procedure B:

Step 2: A mixture of2-(2-methoxy-4-nitrophenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(736 mg; 2.41 mmol) and 1:1 1N HCl:MeOH (25 mL) was treated with Zn dust(789 mg; 12.1 mmol), slowly to the mixture over a period of 1 hour. Thereaction was quenched with 2N NaOH and then extracted with CH₂Cl₂. Theorganic extracts were concentrated and2-(4-amino-2-methoxyphenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dionewas used without further purification, 1.2.1.

LCMS: 88% @254 nm, R_(T)=1.25 min., m/z=276 [M+H]⁺

Procedure C:

Step 3: To a mixture of2-(4-amino-2-methoxyphenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione(250 mg; 0.908 mmol) in DMF (5 mL) was added DIEA (316 μL; 1.82 mmol)followed by picolinyl chloride HCl (194 mg; 1.09 mmol). The reactionmixture was stirred at 50° C. overnight and then cooled to rt and washedwith CH₂Cl₂ and H₂O. The organic layer was concentrated and purified byflash column chromatography (EtOAc) yieldingN-(4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)-3-methoxyphenyl)picolinamide,1.3.1.

LCMS: >98% @254 nm, R_(T)=1.85 min., m/z=381.1 [M+H]⁺

Example 1.3.2N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)picolinamide

Step 1: Example 1.1.2,2-(2-chloro-4-nitrophenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione,was prepared in a manner similar to 1.1.1.

LCMS: >98% @254 nm, R_(T)=2.79 min., m/z=310 [M+H]⁺

Step 2: Example 1.2.2,2-(4-amino-2-chlorophenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione,was prepared in a manner similar to 1.2.1.

LCMS: >98% @254 nm, R_(T)=1.58 min., m/z=280 [M+H]⁺

Step 3: Example 1.3.2,N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=2.82 min., m/z=385 [M+H]⁺

HRMS calc'd for C₁₉H₁₈N₄O₃Cl: 385.1067. found: 385.1067 [M+H]⁺.

¹H NMR (DMSO-d₆) δ11.0 (s, 1 H), 8.78 (d, 1 H, J=3.3 Hz), 8.28 (dd, 1 H,J=5.7, 1.8 Hz), 8.19 (d, 1 H, J=5.7 Hz), 8.10 (td, 1 H, J=5.7, 1.2 Hz),8.00 (td, 1 H, J=6.6, 1.8 Hz), 7.74-7.70 (m, 1 H), 7.46 (dd, 1 H,J=11.7, 6.3 Hz), 4.21-4.16 (m, 1 H), 4.02-3.98 (m, 1 H), 2.98-2.89 (m, 1H), 2.16-2.08 (m, 1 H), 1.94-1.90 (m, 1 H), 1.59-1.52 (m, 1.5 H),1.41-1.32 (m, 1.5 H).

Example 1.3.3N-(4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)picolinamide

Step 1: Example 1.3.3,N-(4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >92% @254 nm, R_(T)=2.65 min., m/z=373.1 [M+Na]⁺

Example 1.3.4N-(3-Chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-6-fluoropicolinamide(TFA)

Procedure D:

Step 1: To a stirred solution of2-(4-amino-2-chlorophenyl)tetrahydroimidazo[1,5-α]pyridine-1,3(2H,5H)-dione(0.03 g, 0.107 mmol), HATU (0.045 g, 0.119 mmol), DIEA (0.041 mL, 0.236mmol) in DMF (1 mL) was added 2-fluoro-6-pyridine carboxylic acid (0.017g, 0.118 mmol). The reaction mixture was stirred at room temperature for15 h. The reaction was diluted with water (4 mL) and extracted withethyl acetate (2×3 mL). The organic extracts were combined andconcentrated. The residue was purified by reverse phase HPLC to giveN-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-6-fluoropicolinamide(TFA), 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.85 min., m/z=403.1 [M+H]⁺.

Example 1.3.5N-(3-Chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)thiazole-4-carboxamide(TFA)

Step 1: Example 1.3.5,N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)thiazole-4-carboxamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.58 min., m/z=391.1 [M+H]⁺

Example 1.3.6N-(3-Chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)pyrimidine-4-carboxamide

Step 1: Example 1.3.6,N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)pyrimidine-4-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.50 min., m/z=386.1 [M+H]⁺

Example 1.3.7N-(3-Chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-3-fluoropicolinamide(TFA)

Step 1: Example 1.3.7,N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-3-fluoropicolinamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.66 min., m/z=403.1 [M+H]⁺

Example 1.3.85-Chloro-N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)furan-2-carboxamide

Step 1: Example 1.3.8,5-chloro-N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)furan-2-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.85 min., m/z=408.1 [M+H]⁺

Example 1.3.9N-(3-chloro-4-(1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H,5H,6H,7H,7aH)-yl)phenyl)picolinamide

Step 1: Example 1.1.9,2-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dionethat was taken to the next step without purification, was prepared in amanner similar to 1.1.1.

LCMS: >98% @254 nm, R_(T)=1.25 min., m/z=295.8 [M+H]⁺

Step 2: Example 1.2.9,2-(4-aminophenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dionethat was taken to the next step without purification, was prepared in amanner similar to 1.2.1.

LCMS: >56% @254 nm, R_(T)=0.93 min., m/z=265.9 [M+H]⁺

Step 3: Example 1.3.9,N-(3-chloro-4-(1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H,5H,6H,7H,7aH)-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.29 min., m/z=371.0 [M+H]⁺

Example 1.3.10N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)phenyl)picolinamide

Step 1: Example 1.1.10,2-(2-chloro-4-nitrophenyl)-3-thioxohexahydroimidazo[1,5-a]pyridin-1(5H)-one,was prepared in a manner similar to 1.1.1.

LCMS: >98% @254 nm, R_(T)=3.14 min., m/z=326 [M+H]⁺

Step 2: Example 1.2.10,2-(4-amino-2-chlorophenyl)-3-thioxohexahydroimidazo[1,5-a]pyridin-1(5H)-one,was prepared in a manner similar to 1.2.1.

LCMS: >98% @254 nm, R_(T)=2.55 min., m/z=296 [M+H]⁺

Step 3: Example 1.3.10,N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)phenyl)picolinamide, was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=3.13 min., m/z=401 [M+H]⁺

Example 1.3.11N-(3-chloro-4-(3-methyl-2,5-dioxoimidazolin-1-yl)phenyl)picolinamide

Step 1: Example 1.1.11,3-(2-chloro-4-nitrophenyl)-1-methylimidazolidine-2,4-dione, was preparedin a manner similar to 1.1.1.

LCMS: >98% @254 nm, R_(T)=2.38 min., m/z=270 [M+H]⁺

Step 2: Example 1.2.11,3-(4-amino-2-chlorophenyl)-1-methylimidazolidine-2,4-dione which wasused without further purification, was prepared in a manner similar to1.2.1.

Step 3: Example 1.3.11,N-(3-chloro-4-(3-methyl-2,5-dioxoimidazolin-1-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=2.50 min., m/z=345 [M+H]⁺

Example 1.3.12N-(3-chloro-4-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)phenyl)picolinamide

Step 1: Example 1.1.12,3-(2-chloro-4-nitrophenyl)-1,3-diazaspiro[4.5]decane-2,4-dione, wasprepared in a manner similar to 1.1.1.

LCMS: >98% @254 nm, R_(T)=2.96 min., m/z=324 [M+H]⁺

Step 2: Example 1.2.12,3-(4-amino-2-chlorophenyl)-1,3-diazaspiro[4.5]decane-2,4-dione, wasprepared in a manner similar to 1.2.1.

LCMS: >98% @254 nm, R_(T)=2.39 min., m/z=294 [M+H]⁺

Step 3: Example 1.3.12,N-(3-chloro-4-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)phenyl)picolinamide, was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=2.97 min., m/z=399 [M+H]⁺

Example 1.3.13N-(3-chloro-4-(2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)phenyl)picolinamide

Step 1: Example 1.1.13,3-(2-chloro-4-nitrophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione, wasprepared in a manner similar to 1.1.1.

LCMS: >71% @254 nm, R_(T)=1.27 min., m/z=309.9 [M+H]⁺

Procedure E:

Step 2: 3-(2-chloro-4-nitrophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione(268 mg; 0.87 mmol) was stirred in MeOH (15 mL) and catalytic Rainey-Ni(30 mg) was added. The reaction flask evacuated and purged with Ar. Theflask was then evacuated and purged with hydrogen (1 atm) via balloon.After vigorous stirring for 1 h, the mixture was filtered throughCelite, washed with MeOH and CH₂Cl₂ and the filtrate was concentratedyielding 3-(4-amino-2-chlorophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dionethat was taken to the next step without purification, 1.2.13.

LCMS: >40% @254 nm, R_(T)=0.98 min., m/z=280.0 [M+H]⁺

Step 3: Example 1.3.13,N-(3-chloro-4-(2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)phenyl)picolinamide, was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.30 min., m/z=385.0 [M+H]⁺

Example 1.3.14N-(3-chloro-4-(6,8-dioxo-5,7-diazaspiro[3.4]octan-7-yl)phenyl)picolinamide

Step 1: Example 1.1.14,7-(2-chloro-4-nitrophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, wasprepared in a manner similar to 1.1.1.

LCMS: >88% @254 nm, R_(T)=1.22 min., m/z=295.8 [M+H]⁺

Step 2: Example 1.2.14,7-(4-amino-2-chlorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione, wasprepared in a manner similar to 1.2.13.

Step 3: Example 1.3.14,N-(3-chloro-4-(6,8-dioxo-5,7-diazaspiro[3.4]octan-7-yl)phenyl)picolinamide, was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.26 min., m/z=371.0 [M+H]⁺

Example 1.3.15N-(3-chloro-4-(2,4-dioxo-1,3-diazaspiro[4.6]undecan-3-yl)phenyl)picolinamide

Procedure F:

Step 1: A mixture of 1-aminocycloheptanecarboxylic acid (125 mg, 0.8mmol) and DMF (0.8 mL) was treated with DBU (0.119 mL, 0.8 mmol) andallowed to stir for 5 min. The solution was then treated with2-chloro-4-nitrophenylisocyanate (237 mg, 1.2 mmol) in DCE (2 ml) andthe resulting mixture was allowed to stir for 30 min at ambienttemperature and then reacted in a microwave vessel at 160° C. for 10min. The reaction mixture was then cooled to rt, diluted with CH₂Cl₂ andthen extracted with water, 1N HCl, sat. aq. NaHCO₃, and the solventremoved under reduced pressure. The crude residue was re-crystallizedfrom hot MeOH to afford 51 mg of3-(2-chloro-4-nitrophenyl)-1,3-diazaspiro[4.6]undecane-2,4-dione,1.1.15, (18%).

¹H NMR (CDCl₃) δ 8.4 (s, 1 H), 8.2 (d, 1 H, J=8.7 Hz), 7.5 (d, 1 H,J=8.6 Hz), 6.0 (broad s, 1 H), 2.2-2.1 (m, 2 H), 1.9 (m, 5 H), 1.8 (m, 5H).

Step 2: Example 1.2.15,3-(4-amino-2-chlorophenyl)-1,3-diazaspiro[4.6]undecane-2,4-dione, wasprepared in a manner similar to 1.2.13.

Step 3: Example 1.3.15, N-(3-chloro4-(2,4-dioxo-1,3-diazaspiro[4.6]undecan-3-yl)phenyl) picolinamide, wasprepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T=1.30) min., m/z=413 [M+H]⁺

¹H NMR (DMSO-d₆) δ 11.1 (s, 1 H), 8.9 (s, 1H), 8.8 (d, 1 H, J=4.3 Hz),8.3 (d, 1 H, J=2.2 Hz), 8.2 (d, 1 H, J=7.8 Hz), 8.1 (m, 1 H), 8.0 (m, 1H), 7.7 (m, 1 H), 7.5 (d, 1H, J=8.6 Hz), 2.3 (m, 2 H), 2.2 (m, 2 H), 1.7(m, 8 H).

Example 1.3.16(S)-N-(3-chloro-4-(4-isobutyl-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide

Step 1: Example 1.1.16,((S)-3-(2-chloro-4-nitrophenyl)-5-isobutyl-5-methylimidazolidine-2,4-dione,was prepared in a manner similar to 1.1.15.

LCMS: >98% @254 nm, R_(T)=1.22 min., m/z=311.

Step 2: Example 1.2.16,(S)-3-(4-amino-2-chlorophenyl)-5-isobutyl-5-methylimidazolidine-2,4-dione,was prepared in a manner similar to 1.2.13.

Step 3: Example 1.3.16,(S)-N-(3-chloro-4-(4-isobutyl-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.38 min., m/z=387 [M+H]⁺

¹H NMR (CDCl₃) δ 10.1 (s, 1 H), 8.5 (d, 1 H, J=4.4 Hz), 8.2 (d, 1 H,J=7.8 Hz), 8.0 (m, 1 H), 7.8 (m, 1 H), 7.6 (d, 1 H, J=8.6 Hz), 7.4 (m, 1H), 7.2 (m, 1 H), 5.7 (d, 1 H, J=27 Hz), 2.1 (m, 1 H), 1.5 (m, 3 H), 1.0(m, 6 H).

Example 1.3.17(R)-N-(3-chloro-4-(4-isobutyl-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide

Step 1: Example 1.1.17,(R)-3-(2-chloro-4-nitrophenyl)-5-isobutyl-5-methylimidazolidine-2,4-dione,was prepared in a manner similar to 1.1.15.

LCMS: >98% @254 nm, R_(T)=1.29 min., m/z=312 [M+H]⁺

¹H NMR (CDCl₃) δ 8.4 (d, 1 H, J=1 Hz), 8.2 (m, 1H), 7.5 (m, 1 H), 5.7(d, 1 H, J=14.8 Hz), 2.1 (m, 1 H), 1.6 (m, 3 H), 1.1 (m, 6 H).

Step 2: Example 1.2.17,(R)-3-(4-amino-2-chlorophenyl)-5-isopropyl-5-methylimidazolidine-2,4-dione,was prepared in a manner similar to 1.2.13.

Step 3: Example 1.3.17,(R)-N-(3-chloro-4-(4-isobutyl-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.19 min., m/z=387 [M+H]⁺

Example 1.3.18N-(3-chloro-4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide

Step 1: Example 1.1.18,3-(2-chloro-4-nitrophenyl)-5,5-dimethylimidazolidine-2,4-dione, wasprepared in a manner similar to 1.1.15.

LCMS: >98% @254 nm, R_(T)=1.14 min., m/z=284 [M+H]⁺

¹H NMR (DMSO-d₆) δ 8.82 (s, 1 H), 8.5 (d, 1 H, J=2.1 Hz), 8.4 (m, 1 H),7.9 (m, 1 H), 1.5 (d, 6 H, J=9.5 Hz).

Step 2: Example 1.2.18,3-(4-amino-2-chlorophenyl)-5,5-dimethylimidazolidine-2,4-dione, wasprepared in a manner similar to 1.2.13.

Step 3: Example 1.3.18,N-(3-chloro-4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.21 min., m/z=359 [M+H]⁺

¹H NMR (DMSO-d₆) δ 11.1 (s, 1 H), 8.8 (d, 1 H, J=4.2 Hz), 8.6 (s, 1 H),8.3 (s, 1 H), 8.2 (d, 1 H, J=7.8 Hz), 8.1 (m, 1 H), 8.0 (m, 1 H), 7.7(m, 1 H), 7.5 (d, 1 H, J=8.7 Hz), 1.5 (d, 6 H, J=6.1 Hz).

Example 1.3.19(R)-N-(4-(4-Benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamide

Step 1: Example 1.1.19,(R)-5-benzyl-3-(2-chloro-4-nitrophenyl)-5-methylimidazolidine-2,4-dione,was prepared in a manner similar to 1.1.15.

LCMS: >98% @254 nm, R_(T)=1.28 min., m/z=360 [M+H]⁺

Step 2: Example 1.2.19,(R)-3-(4-amino-2-chlorophenyl)-5-benzyl-5-methylimidazolidine-2,4-dione,was prepared in a manner similar to 1.2.13.

Step 3: Example 1.3.19,(R)—N-(4-(4-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: 96% @254 nm, R_(T)=1.30 min., m/z=435 [M+H]⁺

Example 1.3.20(S)-N-(4-(4-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamide

Step 1: Example 1.1.20,(S)-5-benzyl-3-(2-chloro-4-nitrophenyl)-5-methylimidazolidine-2,4-dione,was prepared in a manner similar to 1.1.15.

LCMS: >98% @254 nm, R_(T)=1.28 min., m/z=359 [M+H]⁺

Step 2: Example 1.2.20,(S)-3-(4-amino-2-chlorophenyl)-5-benzyl-5-methylimidazolidine-2,4-dione,was prepared in a manner similar to 1.2.13.

Step 3: Example 1.3.20,(S)-N-(4-(4-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.38 min., m/z=435 [M+H]⁺

Example 1.3.21N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide

Procedure F:

Step 1: To a stirred solution of 3-morphline carboxylic acid (0.100 g;0.627 mmol), DBU (187 μL; 1.25 mmol) in 1,2-dichloroethane (2.8 mL) wasadded 2-chloro-4-nitrophenylisocyanate (0.149 g; 0.752 mmol) and theresulting mixture was heated at 160° C. in the microwave for 10 min. Thereaction was diluted with methylene chloride (15 mL), washed with 1N HCl(10 mL), sat. NaHCO₃ (10 mL) and concentrated under vacuum to give thecrude product. The residue was purified by column chromatography elutingwith ethyl acetate/hexanes 0 to 40% to give 106 mg of2-(2-chloro-4-nitrophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]oxazine-1,3(2H)-dione,1.1.21, (54%).

LCMS: >98% @254 nm, R_(T)=1.14 min., m/z=312 [M+H]⁺

Procedure G:

Step 2: To a stirred solution of2-(2-chloro-4-nitrophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]oxazine-1,3(2H)-dione(0.106 g, 0.341 mmol) in ethanol (5 mL) was added tin (II) chloride(0.323 g, 1.70 mmol) and the reaction mixture was heated at 80° C. for15 h. The reaction was cooled to room temperature, quenched with sat.NaHCO₃, and the white precipitate was filtered. The filtrate waspartitioned between ethyl acetate (20 mL) and brine (15 mL). The organicphase was separated, dried (MgSO₄), filtered and concentrated to givethe crude product. The residue was purified by column chromatographyeluting with ethyl acetate/hexanes 0 to 70% to give 84 mg of2-(4-amino-2-chlorophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]oxazine-1,3(2H)-dione,1.2.21, (88%).

LCMS: >98% @254 nm, R_(T)=1.20 min., m/z=282 [M+H]⁺

Step 3: Example 1.3.21,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @214 nm, R_(T)=2.59 min., m/z=391 [M+H]⁺

Example 1.3.22N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-3-fluoropicolinamide(TFA)

Step 1: Example 1.3.22,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-3-fluoropicolinamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.49 min., m/z=405 [M+H]⁺

Example 1.3.236-Chloro-N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide(TFA)

Step 1: Example 1.3.23,6-chloro-N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.84 min., m/z=421.1 [M+H]⁺

Example 1.3.24N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiophene-2-carboxamide

Step 1: Example 1.3.24,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiophene-2-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.63 min., m/z=392.1 [M+H]⁺

Example 1.3.25N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiazole-2-carboxamide(TFA)

Step 1: Example 1.3.25,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiazole-2-carboxamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.56 min., m/z=393.1 [M+H]⁺

Example 1.3.26N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiazole-4-carboxamide(TFA)

Step 1: Example 1.3.26,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiazole-4-carboxamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.42 min., m/z=393.1 [M+H]⁺

Example 1.3.27N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-3,5-difluoropicolinamide(TFA)

Step 1: Example 1.3.27,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-3,5-difluoropicolinamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.59 min., m/z=423.1 [M+H]⁺

Example 1.3.285-Chloro-N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)furan-2-carboxamide

Step 1: Example 1.3.28,5-chloro-N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)furan-2-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.69 min., m/z=410.0 [M+H]⁺

Example 1.3.29N-(3-Chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-6-fluoropicolinamide(TFA)

Step 1: Example 1.3.29,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-6-fluoropicolinamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.71 min., m/z=405.1 [M+H]⁺

Example 1.3.30N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide

Step 1: Example 1.1.30,2-(4-amino-2-chlorophenyl)-3-thioxohexahydroimidazo[1,5-a]pyridin-1(5H)-one,was prepared in a similar manner to 1.1.21.

LCMS: >98% @254 nm, R_(T)=1.29 min., m/z=328 [M+H]⁺

Step 2: Example 1.2.30,2-(4-amino-2-chlorophenyl)-3-thioxohexahydroimidazo[1,5-a]pyridin-1(5H)-one,was prepared in a manner similar to 1.2.21.

LCMS: >98% @254 nm, R_(T)=1.20 min., m/z=282 [M+H]⁺

Step 3: Example 1.3.30,N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.4.

LCMS: 93.0% @214 nm, R_(T)=2.93 min., m/z=403 [M+H]⁺

Example 1.3.31N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)pyrazine-2-carboxamide

Step 1: Example 1.3.31,N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)pyrazine-2-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.68 min., m/z=404.1 [M+H]⁺

Example 1.3.32 6-ChloroN-(3-chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)picolinamide

Step 1: Example 1.3.32,6-chloro-N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)picolinamide (TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=3.11 min., m/z=437.0 [M+H]⁺

Example 1.3.33N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiophene-2-carboxamide

Step 1: Example 1.3.33,N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)thiophene-2-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.90 min., m/z=408.0 [M+H]⁺

Example 1.3.34N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiazole-2-carboxamide

Step 1: Example 1.3.34,N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)thiazole-2-carboxamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.86 min., m/z=409.0 [M+H]⁺

Example 1.3.35N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)thiazole-4-carboxamide

Step 1: Example 1.3.35,N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)thiazole-4-carboxamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T) 2.73 min., m/z=409.0 [M+H]⁺

Example 1.3.36N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-3,5-difluoropicolinamide

Step 1: Example 1.3.36,N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-3,5-difluoropicolinamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.89 min., m/z=439.1[M+H]⁺

Example 1.3.375-Chloro-N-(3-chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-furan-2-carboxamide

Step 1: Example 1.3.37,5-chloro-N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)furan-2-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.98 min., m/z=426.0 [M+H]⁺

Example 1.3.38N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-6-fluoropicolinamide

Step 1: Example 1.3.38,N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-6-fluoropicolinamide(TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.99 min., m/z 421.1 [M+H]⁺

Example 1.3.39N-(3-Chloro-4-(1-oxo-3-thioxodihydro-1H-imidazo[5,1-c][1,4]oxazin-2(3H,8H,8aH)-yl)phenyl)-3-fluoropicolinamide

Step 1: Example 1.3.39,N-(3-chloro-4-(1-oxo-3-thioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-3-fluoropicolinamide (TFA), was prepared in a manner similar to 1.3.4.

LCMS: >98% @214 nm, R_(T)=2.77 min., m/z=421.1 [M+H]⁺

Example 1.3.40N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,8aH)-yl)phenyl)picolinamide

Step 1: Example 1.1.40,2-(2-chloro-4-nitrophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]thiazine-1,3(2H)-dione,was prepared in a manner similar to 1.1.1.

LCMS: >98% @254 nm, R_(T)=1.30 min., m/z=327.8 [M+H]⁺

¹H NMR (400 MHz, CDCl₃): δ 8.42 (d, 1 H, J=2.4 Hz), 8.26-8.23 (m, 1 H),7.53-7.50 (m, 1 H), 4.55-4.51 (m, 1 H), 4.35-4.25 (m, 1 H), 3.29-3.20(m, 1 H), 3.09-3.06 (m, 1 H), 2.85-2.73 (m, 2 H), 2.66-2.62 (m, 1 H).

Procedure H:

Step 2: The2-(2-chloro-4-nitrophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]thiazine-1,3(2H)-dione(124 mg, 0.38 mmol) and 5% Pt sulfided on carbon (148 mg, 0.04 mmol)were added to a flask under argon. Methanol (8 mL) was added. The flaskwas purged with vacuum and H₂ gas, then H₂ gas was applied by balloon (1atm) with stirring for about 18 hours. The mixture was diluted with MeOHand poured through Celite, washing with MeOH. The filtrate wasconcentrated under vacuum to give about 125 mg of crude product. Thecompound was purified by chromatography on silica gel (12 g) elutingwith a 0-to-50% A-to-B gradient (A is DCM: B is 10% MeOH/DCM with 1%ammonium hydroxide) to give 67 mg of2-(4-amino-2-chlorophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]thiazine-1,3(2H)-dione,1.2.40.

LCMS: >98% @254 nm, R_(T)=1.02 min., m/z=297.8 [M+H]⁺

¹H NMR (400 MHz, CDCl₃): δ 7.01 (d, 1 H, J=8.6 Hz), 6.78 (d, 1 H, J=2.5Hz), 6.61-6.59 (m, 1 H), 4.54-4.51 (m, 1 H), 4.25-4.16 (m, 1 H), 3.91(s, 2 H), 3.25-3.15 (m, 1 H), 3.06-3.03 (m, 1 H), 2.83-2.68 (m, 2 H),2.61-2.57 (m, 1 H).

Step 3: Example 1.3.40,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,8aH)-yl)phenyl)picolinamide,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.32 min., m/z=402.9 [M+H]⁺

Example 1.3.41N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]dioxothiazin-2(3H,8H,8aH)-yl)phenyl)picolinamide

Procedure I:

Step 1:N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,8aH)-yl)phenyl)picolinamide (60 mg, 0.15 mmol) was stirred in CH₂Cl₂ (2.0 mL) at 0° C.m-CPBA (67 mg, 0.30 mmol, 77%) was added in two equal portions about 5minutes apart. The reaction was stirred about 1 hr at 0° C. then allowedto warm to room temperature and stirred for another 2 hrs. The reactionwas then concentrated and purified by reverse-phase HPLC (15-to-55gradient ACN/Water 0.1% TFA) followed by free basing to give 37 mg ofN-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]dioxothiazin-2(3H,8H,8aH)-yl)phenyl)picolinamide, 1.3.41, (57%).

LCMS: >98% @254 nm, R_(T)=1.24 min., m/z=435.0 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ 11.04 (m, 1 H), 8.77 (d, 1 H, J=4.5 Hz),8.26 (dd, 1 H, J=8.4, 2.3 Hz), 8.17 (d, 1 H, J=7.8 Hz), 8.11-7.99 (m, 2H), 7.72-7.69 (m, 1 H), 7.46-7.40 (m, 1 H), 4.85-4.63 (m, 1 H),4.45-4.40 (m, 1 H), 3.79-3.73 (m, 1 H), 3.69-3.36 (m, 3 H), 3.26 (m, 1H).

Example 1.3.42N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,8aH)-yl)phenyl)-6-fluoropicolinamide

Step 1: Example 1.3.42,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,8aH)-yl)phenyl)thiazole-4-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @254 nm, R_(T)=1.35 min., m/z=420.8 [M+H]⁺

Example 1.3.43N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,8aH)-yl)phenyl)thiazole-4-carboxamide

Step 1: Example 1.3.42,N-(3-chloro-4-(1,3-dioxodihydro-1H-imidazo[5,1-c][1,4]thiazin-2(3H,8H,8aH)-yl)phenyl)thiazole-4-carboxamide,was prepared in a manner similar to 1.3.4.

LCMS: >98% @254 nm, R_(T)=1.25 min., m/z=408.9 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ 10.75 (d, 1 H, J=4.4 Hz), 9.27 (d, 1 H,J=1.9 Hz), 8.57 (s, 1 H), 8.21-8.18 (m, 1 H), 7.96-7.91 (m, 1 H),7.47-7.39 (m, 1 H), 4.46-4.27 (m, 2 H), 3.18-2.64 (m, 5 H).

Example 1.3.44tert-butyl-2-(2-chloro-4-(picolinamide)phenyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate

Step 1: Example 1.1.44, tert-butyl2-(2-chloro-4-nitrophenyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate,was prepared in a manner similar to 1.1.1.

LCMS: >72% @254 nm, R_(T)=1.41 min., m/z=432.8 [M+Na]⁺

¹H NMR (400 MHz, CDCl₃): δ 8.44 (m, 1 H), 8.27-8.24 (m, 1 H), 7.55-7.51(m, 1 H), 4.68 (br. s, 1 H), 4.27-4.14 (m, 3 H), 3.19-3.10 (m, 1 H),2.90-2.80 (m, 2 H), 1.51 (s, 9 H).

Step 2: Example 1.2.44, tert-butyl2-(4-amino-2-chlorophenyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate,was prepared in a manner similar to 1.2.13.

LCMS: >98% @254 nm, R_(T)=1.23 min., m/z=403.1 [M+Na]⁺

¹H NMR (400 MHz, DMSO-d₆): δ 7.04-6.96 (m, 1 H), 6.69 (m, 1 H),6.55-6.53 (m, 1 H), 5.69 (br. s, 2 H), 4.36-4.18 (m, 2 H), 4.03-3.88 (m,2 H), 3.04-2.82 (m, 3 H), 1.43 (s, 9 H).

Step 3: Example 1.3.44, tert-butyl2-(2-chloro-4-(picolinamide)phenyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate,was prepared in a manner similar to 1.3.1.

LCMS: >98% @254 nm, R_(T)=1.23 min., m/z=508.1 [M+Na]⁺

¹H NMR (400 MHz, DMSO-d₆): δ 11.04 (d, 1 H, J=5.4 Hz), 8.75 (d, 1 H,J=4.6 Hz), 8.29-8.25 (m, 1 H), 8.18 (d, 1 H, J=7.8 Hz), 8.11-8.07 (m, 1H), 8.03-7.97 (m, 1 H), 7.72-7.69 (m, 1 H), 7.50-7.43 (m, 1 H),4.47-4.19 (m, 2 H), 4.07-3.92 (m, 2 H), 3.25-2.77 (m, 3 H), 1.44 (s, 9H).

Example 1.3.45N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-phenyl)picolinamide

Procedure J:

Step 1: tert-butyl2-(2-chloro-4-(picolinamide)phenyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate(85 mg, 0.18 mmol) was stirred in the 30% TFA/DCM (5 mL) at roomtemperature for about 2 hrs. The reaction was then concentrated undervacuum. The residue was dissolved in EtOAc and aqueous (saturated)NaHCO₃. The aqueous layer was separated and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, concentrated andpurified by reverse-phase HPLC followed by free-basing the TFA salt togive 65 mg ofN-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-phenyl)picolinamide,1.3.45, (97%).

LCMS: >98% @254 nm, R_(T)=1.00 min., m/z=408.0 [M+Na]⁺

Example 1.3.46N-(3-chloro-4-(7-methyl-1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-yl)phenyl)picolinamide

Procedure K:

Step 1:N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-phenyl)picolinamide (60 mg, 0.16 mmol) was stirred in the dichlroethane (0.56mL) at room temperature. Then 37% formaldehyde (0.017 mL, 0.23 mmol) wasadded, followed by the NaBH(OAc)₃ (63 mg, 0.30 mmol). The mixture wasstirred overnight. The reaction was diluted with CH₂Cl₂ and neutralizedwith aqueous (saturated) NaHCO₃. The organic layer was separated, driedover Na₂SO₄, concentrated, and purified by reverse-phase HPLC(10-to-40gradient ACN/Water 0.1% TFA), followed by free-basing the TFA salt togive 57 mg ofN-(3-chloro-4-(7-methyl-1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-yl)phenyl)picolinamide, 1.3.46, (92%).

LCMS: >98% @254 nm, R_(T)=1.02 min., m/z=422.0 [M+Na]⁺

¹H NMR (400 MHz, DMSO-d₆): δ11.04 (d, 1 H, J=4.2 Hz), 8.76 (d, 1 H,J=4.7 Hz), 8.29-8.25 (m, 1 H), 8.18 (d, 1 H, J=7.8 Hz), 8.11-8.07 (m, 1H), 8.02-7.97 (m, 1 H), 7.72-7.69 (m, 1 H), 7.50-7.42 (m, 1 H),4.44-4.31 (m, 1 H), 3.95-3.88 (m, 1 H), 3.20-3.05 (m, 2 H), 2.83-2.76(m, 1 H), 2.29 (s, 3 H), 2.13-1.87 (m, 2 H).

Example 1.3.47N-(3-chloro-4-(7-(methylsulfonyl)-1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-yl)phenyl)picolinamide

Procedure L:

Step 1:N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-phenyl)picolinamide (38 mg, 0.10 mmol) was stirred in CH₂Cl₂ (0.70 mL) at roomtemperature. Then triethylamine (0.041 mL, 0.30 mmol) was added and thesolution was cooled to 0° C. Then methane sulfonylchloride (0.010 mL,0.12 mmol) was dissolved in CH₂Cl₂ (0.30 mL) and added dropwise to thecooled solution. The reaction was allowed to warm slowly to roomtemperature and stirred for about 3 hrs. The reaction was diluted withCH₂Cl₂ and quenched with water and aqueous (saturated) NaHCO₃. Theorganic layer was separated and the aqueous layer extracted with CH₂Cl₂.The combined organic layers were dried over Na₂SO₄, concentrated, andpurified by reverse-phase HPLC (20-to-60 gradient ACN/Water 0.1% TFA),followed by free-basing the TFA salt to give 45 mg ofN-(3-chloro-4-(7-(methylsulfonyl)-1,3-dioxotetrahydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-yl)phenyl)picolinamide,1.3.47, (99%).

LCMS: >98% @254 nm, R_(T)=1.02 min., m/z=464.0 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ11.05 (d, 1 H, J=4.6 Hz), 8.77 (d, 1 H,J=4.7 Hz), 8.31-8.27 (m, 1 H), 8.19 (d, 1 H, J=7.8 Hz), 8.11-7.98 (m, 2H), 7.73-7.70 (m, 1 H), 7.50-7.46 (m, 1 H), 4.66-4.49 (m, 1 H),4.10-4.05 (m, 1 H), 3.98-3.84 (m, 1 H), 3.70-3.62 (m, 1 H), 3.24-2.85(m, 6 H).

The following table shows biological activity in connection withembodiments of the preset invention in terms of half maximal effectiveconcentration (EC₅₀) (Y=Bottom+(Top−Bottom)/(1+^10((LogEC50−X)*Hillslope)) X=logarithm of concentration, Y is the response).

Biological Activity:

Example Formula MW EC₅₀ 1.3.1  C₂₀H₂₀N₄O₄ 380.397 2.7E−06 1.3.2 C₁₉H₁₇ClN₄O₃ 384.816 8.14E−07 1.3.3  C₂₁H₁₉F₃N₄O₅ 464.395 3.12E−061.3.4  C₂₁H₁₇ClF₄N₄O₅ 516.83 1.67E−06 1.3.5  C₁₇H₁₅ClN₄O₃S 390.8441.98E−06 1.3.6  C₁₈H₁₆ClN₅O₃ 385.804 2.58E−06 1.3.7  C₂₁H₁₇ClF₄N₄O₅516.83 3.31E−06 1.3.8  C₁₈H₁₅Cl₂N₃O₄ 408.235 6.2E−06 1.3.9 C₂₀H₁₆ClF₃N₄O₅ 484.813 2.11E−06 1.3.10 C₂₁H₁₈ClF₃N₄O₄S 514.905 3.67E−071.3.11 C₁₆H₁₃ClN₄O₃ 344.752 7.06E−06 1.3.12 C₂₀H₁₉ClN₄O₃ 398.8432.29E−07 1.3.13 C₂₁H₁₈ClF₃N₄O₅ 498.84 7.95E−07 1.3.14 C₂₀H₁₆ClF₃N₄O₅484.813 1.28E−06 1.3.15 C₂₁H₂₁ClN₄O₃ 412.869 2.22E−07 1.3.16C₂₀H₂₁ClN₄O₃ 400.859 3.59E−06 1.3.17 C₂₀H₂₁ClN₄O₃ 400.859 1.5E−06 1.3.18C₁₇H₁₅ClN₄O₃ 358.779 4.21E−06 1.3.19 C₂₃H₁₉ClN₄O₃ 434.875 8.4E−07 1.3.20C₂₃H₁₉ClN₄O₃ 434.875 6.04E−07 1.3.21 C₁₈H₁₅ClN₄O₄ 386.789 2.18E−061.3.22 C₂₀H₁₅ClF₄N₄O₆ 518.803 5.82E−06 1.3.23 C₂₀H₁₅Cl₂F₃N₄O₆ 535.2584.83E−06 1.3.24 C₁₇H₁₄ClN₃O₄S 391.829 9.5E−06 1.3.25 C₁₈H₁₄ClF₃N₄O₆S506.84 6.32E−06 1.3.26 C₁₈H₁₄ClF₃N₄O₆S 506.84 6.11E−06 1.3.27C₂₀H₁₄ClF₅N₄O₆ 536.793 2.93E−06 1.3.28 C₁₇H₁₃Cl₂N₃O₅ 410.208 8.77E−061.3.29 C₂₀H₁₅ClF₄N₄O₆ 518.803 6.73E−06 1.3.30 C₁₈H₁₅ClN₄O₃S 402.8551.47E−06 1.3.31 C₁₇H₁₄ClN₅O₃S 403.843 3.56E−06 1.3.32 C₂₀H₁₅Cl₂F₃N₄O₅S551.323 1.49E−06 1.3.33 C₁₇H₁₄ClN₃O₃S₂ 407.894 8.46E−06 1.3.34C₁₈H₁₄ClF₃N₄O₅S₂ 522.906 1.17E−06 1.3.35 C₁₈H₁₄ClF₃N₄O₆S 506.84 1.49E−061.3.36 C₂₀H₁₄ClF₅N₄O₅S 552.859 1.68E−06 1.3.37 C₁₇H₁₃Cl₂N₃O₄S 426.2745.05E−06 1.3.38 C₂₀H₁₅ClF₄N₄O₅S 534.869 9.33E−07 1.3.39 C₂₀H₁₅ClF₄N₄O₅S534.869 1.2E−06 1.3.40 C₁₈H₁₅ClN₄O₃S 402.855 4.03E−07 1.3.41C₁₈H₁₅ClN₄O₅S 434.854 3.03E−06 1.3.42 C₁₈H₁₄ClFN₄O₃S 420.845 1.17E−061.3.43 C₁₆H₁₃ClN₄O₃S₂ 408.882 3.76E−06 1.3.44 C₂₃H₂₄ClN₅O₅ 485.927.54E−07 1.3.45 C₁₈H₁₆ClN₅O₃ 385.804 4.2E−06 1.3.46 C₁₉H₁₈ClN₅O₃ 399.8311.3.47 C₁₉H₁₈ClN₅O₅S 463.895 4.71E−06

Further examples include the following:

Example 1.3.48N-(3-chloro-4-(8a-methyl-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)picolinamideExample 1.3.49N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)picolinamideExample 1.3.50N-(4-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)phenyl)picolinamideExample 1.3.51N-(3-chloro-4-(2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenyl)picolinamideExample 1.3.52N-(3-chloro-4-(1-methyl-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)phenyl)picolinamideExample 1.3.53N-(3-chloro-4-(2′,5′-dioxospiro[bicyclo[2.2.1]heptane-2,4′-imidazolidin]-1′-yl)phenyl)picolinamideExample 1.3.54N-(3-chloro-4-(3′-methyl-2′,5′-dioxospiro[bicyclo[2.2.1]heptane-2,4′-imidazolidin]-1′-yl)phenyl)picolinamideExample 1.3.55N-(4-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)phenyl)furan-2-carboxamideExample 1.3.56(S)-N-(3-chloro-4-(2,5-dioxo-4-phenylimidazolidin-1-yl)phenyl)picolinamideExample 1.3.57(S)-N-(4-(4-(tert-butyl)-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamideExample 1.3.58(S)-N-(4-(4-(tert-butyl)-3-isopropyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamideExample 1.3.59(S)-N-(3-chloro-4-(4-isopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamideExample 1.3.60(R)-N-(3-chloro-4-(4-isopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamideExample 1.3.61(S)-N-(3-chloro-4-(4-(4-fluorobenzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamideExample 1.3.62(S)-N-(3-chloro-4-(4-(4-fluorobenzyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamideExample 1.3.63(S)-N-(4-(4-(4-fluorobenzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-methoxyphenyl)picolinamideExample 1.3.64(S)-N-(4-(4-benzyl-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamideExample 1.3.65(S)-N-(4-(4-benzyl-3-ethyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)picolinamideExample 1.3.66(S)-N-(4-(4-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)-3,5-difluoropicolinamideExample 1.3.67(S)-N-(4-(4-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)thiazole-2-carboxamideExample 1.3.68(S)-N-(4-(4-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)-6-methoxypicolinamideExample 1.3.69(S)-N-(4-(4-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-chlorophenyl)-6-fluoropicolinamideExample 1.3.70N-(3-chloro-4-(4-cyclohexyl-2,5-dioxoimidazolidin-1-yl)phenyl)picolinamideExample 1.3.71N-(3-chloro-4-(7-cyclohexyl-1,3-dioxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)phenyl)picolinamideExample 1.3.72N-(4-(7-acetyl-1,3-dioxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)-3-chlorophenyl)picolinamideExample 1.3.73N-(3-chloro-4-(1,3-dioxo-7-pivaloylhexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)phenyl)picolinamideExample 1.3.74N-(3-chloro-4-(7-(furan-2-carbonyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)phenyl)picolinamideExample 1.3.756-chloro-N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)picolinamideExample 1.3.76N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)pyrazine-2-carboxamideExample 1.3.77N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)thiophene-2-carboxamideExample 1.3.78N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)thiophene-3-carboxamideExample 1.3.79N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)thiazole-2-carboxamideExample 1.3.80N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)thiazole-4-carboxamideExample 1.3.81N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-3,5-difluoropicolinamideExample 1.3.825-chloro-N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)furan-2-carboxamideExample 1.3.83N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-6-fluoropicolinamideExample 1.3.84N-(3-chloro-4-(1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-3-fluoropicolinamideExample 1.3.856-chloro-N-(3-chloro-4-(8a-methyl-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)picolinamideExample 1.3.86N-(3-chloro-4-(8a-methyl-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)thiazole-2-carboxamideExample 1.3.87N-(3-chloro-4-(8a-methyl-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)thiazole-4-carboxamideExample 1.3.88N-(3-chloro-4-(8a-methyl-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-3,5-difluoropicolinamideExample 1.3.895-chloro-N-(3-chloro-4-(8a-methyl-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)furan-2-carboxamideExample 1.3.90N-(3-chloro-4-(8a-methyl-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-6-fluoropicolinamideExample 1.3.91N-(3-chloro-4-(8a-methyl-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-3-fluoropicolinamideExample 1.3.92N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)pyrazine-2-carboxamideExample 1.3.936-chloro-N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)picolinamideExample 1.3.94N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)thiazole-2-carboxamideExample 1.3.95N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)thiazole-4-carboxamideExample 1.3.96N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-3,5-difluoropicolinamideExample 1.3.975-chloro-N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)furan-2-carboxamideExample 1.3.98N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-6-fluoropicolinamideExample 1.3.99N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)-3-fluoropicolinamideExample 1.3.100N-(3-chloro-4-(8a-methyl-1-oxo-3-thioxohexahydroimidazo[1,5-a]pyridin-2(3H)-yl)phenyl)pyridazine-3-carboxamide

Biological Activity:

Example Formula MW EC50 1.3.48 C₂₀H₁₉ClN₄O₃ 398.84 4.34E−07 1.3.49C₂₀H₁₉ClN₄O₂S 414.90 1.85E−07 1.3.50 C₂₁H₁₉F₃N₄O₃ 432.4 4.54E−07 1.3.51C₂₆H₂₃ClN₄O₃ 475.00 2.14E−06 1.3.52 C₂₁H₂₁ClN₄O₃ 412.87 1.78E−07 1.3.53C₂₁H₁₉ClN₄O₃ 410.85 2.17E−07 1.3.54 C₂₂H₂₁ClN₄O₃ 424.88 3.25E−07 1.3.55C₂₀H₁₈F₃N₃O₄ 421.4 4.12E−06 1.3.56 C₂₁H₁₅ClN₄O₃ 406.82 3.80E−07 1.3.57C₁₉H₁₉ClN₄O₃ 386.83 2.00E−07 1.3.58 C₂₂H₂₅ClN₄O₃ 428.91 2.00E−07 1.3.59C₁₉H₁₉ClN₄O₃ 386.83 1.50E−06 1.3.60 C₁₉H₁₉ClN₄O₃ 386.83 3.59E−06 1.3.61C₂₃H₁₈ClFN₄O₃ 452.87 3.35E−07 1.3.62 C₂₄H₂₀ClFN₄O₃ 466.89 2.17E−071.3.63 C₂₄H₂₁FN₄O₄ 448.45 1.04E−06 1.3.64 C₂₄H₂₁ClN₄O₃ 448.90 1.97E−071.3.65 C₂₅H₂₃ClN₄O₃ 462.93 2.36E−07 1.3.66 C₂₃H₁₇ClF₂N₄O₃ 470.862.96E−06 1.3.67 C₂₁H₁₇ClN₄O₃S 440.90 6.11E−06 1.3.68 C₂₄H₂₁ClN₄O₄ 464.905.88E−06 1.3.69 C₂₃H₁₈ClFN₄O₃ 452.87 1.63E−06 1.3.70 C₂₁H₂₁ClN₄O₃ 412.907.43E−07 1.3.71 C₂₄H₂₆ClN₅O₃ 467.95 2.23E−06 1.3.72 C₂₀H₁₈ClN₅O₄ 427.804.51E−06 1.3.73 C₂₃H₂₄ClN₅O₄ 469.9 1.07E−06 1.3.74 C₂₃H₁₈ClN₅O₅ 479.99.67E−07 1.3.75 C₁₉H₁₆Cl₂N₄O₂S 435.4 3.26E−06 1.3.76 C₁₈H₁₆ClN₅O₂S 401.95.04E−06 1.3.77 C₁₈H₁₆ClN₃O₂S₂ 405.9 2.78E−06 1.3.78 C₁₈H₁₆ClN₃O₂S₂405.9 1.79E−06 1.3.79 C₁₇H₁₅ClN₄O₂S₂ 406.9 1.34E−06 1.3.80C₁₇H₁₅ClN₄O₂S₂ 406.9 1.97E−06 1.3.81 C₁₉H₁₅ClF₂N₄O₂S 436.9 8.76E−071.3.82 C₁₈H₁₅Cl₂N₃O₃S 424.5 2.85E−06 1.3.83 C₁₉H₁₆ClFN₄O₂S 418.93.54E−07 1.3.84 C₁₉H₁₆ClFN₄O₂S 418.90 9.93E−07 1.3.85 C₁₉H₁₆Cl₂N₄O₃433.3 8.64E−07 1.3.86 C₁₈H₁₇ClN₄O₃S 404.9 1.63E−06 1.3.87 C₁₈H₁₇ClN₄O₃S404.9 2.67E−06 1.3.88 C₂₀H₁₇ClF₂N₄O₃ 434.90 1.10E−06 1.3.89C₁₉H₁₇Cl₂N₃O₄ 422.3 4.67E−06 1.3.90 C₂₀H₁₈ClFN₄O₃ 416.90 1.12E−06 1.3.91C₂₀H₁₈ClFN₄O₃ 416.90 3.79E−06 1.3.92 C₁₉H₁₈ClN₅O₂S 415.90 1.91E−061.3.93 C₂₀H₁₈Cl₂N₄O₂S 449.40 2.40E−06 1.3.94 C₁₈H₁₇ClN₄O₂S₂ 420.947.61E−07 1.3.95 C₁₈H₁₇ClN₄O₂S₂ 420.94 1.05E−06 1.3.96 C₂₀H₁₇ClF₂N₄O₂S450.90 2.95E−07 1.3.97 C₁₉H₁₇Cl₂N₃O₃S 438.33 8.28E−07 1.3.98C₂₀H₁₈ClFN₄O₂S 432.90 4.70E−07 1.3.99 C₂₀H₁₈ClFN₄O₂S 432.90 6.50E−07 1.3.100 C₁₉H₁₈ClN₅O₂S 415.90 1.90E−06

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otheraspects of the invention will be apparent to those skilled in the artfrom consideration of the specification and practice of the inventiondisclosed herein. It is intended that the specification and examples beconsidered as exemplary only, with a true scope and spirit of theinvention being indicated by the following claims.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as reaction conditions, and so forth usedherein are to be understood as being modified in all instances by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the herein are approximations that mayvary depending upon the desired properties sought to be determined bythe present invention.

What is claimed is:
 1. A compound having a structure represented by aformula:

wherein A is selected from O or S; wherein R₁ is pyridine, pyrimidine,thiazole, furan, thiophene, or pyrazine, optionally substituted with oneor more R₈, aryl, or a 3-8 membered ring containing C, O, S or N,optionally substituted with one or more R₈; wherein R₄ is selected fromH, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionally substitutedwith one or more R₇; wherein R₄ and R₅ may cyclize to form a 3-8membered ring containing C, O, S or N, optionally substituted with oneor more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a 3-7 membered ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈, R₅ and R₆ may cyclize toform a 3-7 membered ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl , aryl, heteroaryl, CN or CF₃; andwherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, CN, OC₁₋₆ alkyl, CF₃, or a pharmaceutically acceptable saltthereof.
 2. A compound of claim 1, where R₁ is pyridine, optionallysubstituted with at least one fluoro, chloro and/or methoxy.
 3. Acompound of claim 1, where R₁ is furan, optionally chloro-substituted.4. A compound of claim 1, where R₆ is methyl.
 5. A compound of claim 1,where R₄ is hydrogen, methyl, alkyl.
 6. A compound of claim 1, where R₇is chloro, CF₃, alkoxy.
 7. A compound of claim 1, where R₅ and R₆ areindependently hydrogen, alkyl, cyclohexyl, methyl.
 8. A compound ofclaim 7, wherein R₅ is ethyl benzyl, tert-butyl carboxylate, acetyl,tert-butyl acetyl, furan acetyl.
 9. A compound of claim 1, where R₄ andR₅ cyclize to form a substituted or unsubstituted 5 or 6 membered ring.10. A compound of claim 1, where R₅ and R₆ cyclize to form a substitutedor unsubstituted 5, 6, 7, or 8 membered ring.
 11. A compound of claim 1,having a structure represented by a formula:


12. A compound of claim 1, having a structure represented by a formula:

wherein R₉ is C, O, S, SO₂, SO₂—C.
 13. A compound of claim 1, of thefollowing formula, or a pharmaceutically acceptable salt thereof:


14. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound having a structure represented by a formula:

wherein A is selected from O or S; wherein R₁ is pyridine, pyrimidine,thiazole, furan, thiophene, pyrazine, optionally substituted with one ormore R₈, aryl, or a 3-8 membered ring containing C, O, S or N,optionally substituted with one or more R₈; wherein R₄ is selected fromH, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionally substitutedwith one or more R₇; wherein R₄ and R₅ may cyclize to form a 3-8membered ring containing C, O, S or N, optionally substituted with oneor more R₈; wherein R₅ is selected from: H, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, aryl, heteroaryl optionally substituted with one or more R₈;wherein R₅ and R₆ may cyclize to form a 3-7 membered ring containing C,O, S or N, optionally substituted with one or more R₈; wherein R₆ isselected from: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryloptionally substituted with one or more R₈, R₅ and R₆ may cyclize toform a 3-7 membered ring containing C, O, S or N, optionally substitutedwith one or more R₇; wherein R₇ is selected from: H, halogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, OC₁₋₆ alkyl , aryl, heteroaryl, CN or CF₃; andwherein R₈ is selected from OH, NR₁R₂, halogen, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, CN, OC₁₋₆ alkyl, CF₃, or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier.
 15. A composition ofclaim 14, where R₁ is pyridine, optionally substituted with at least onefluoro, chloro and/or methoxy.
 16. A composition of claim 14, where R₁is furan, optionally chloro-substituted.
 17. A composition of claim 14,where R₆ is methyl.
 18. A composition of claim 14, where R₄ is hydrogen,methyl, alkyl.
 19. A composition of claim 14, where R₇ is chloro, CF₃,alkoxy.
 20. A composition of claim 14, where R₅ and R₆ are independentlyhydrogen, alkyl, cyclohexyl, methyl.
 21. A composition of claim 14,where R₄ and R₅ cyclize to form a substituted or unsubstituted 5 or 6membered ring.
 22. A composition of claim 14, where R₅ and R₆ cyclize toform a substituted or unsubstituted 5, 6, 7,or 8 membered ring.
 23. Acomposition of claim 14, having a structure represented by a formula:


24. A composition of claim 14, having a structure represented by aformula:

wherein R₉ is C, O, S, SO₂, SO₂—C.
 25. A composition of claim 14, of thefollowing formula, or a pharmaceutically acceptable salt thereof:


26. A compound of claim 1, of the following formula:


27. A compound of claim 11, wherein R₇ is H or Cl.
 28. A compound ofclaim 12, wherein R₇ is H or Cl.
 29. A compound of claim 11, wherein R₄is H or CH₃; R₇ is H or Cl; R₆ is CH₃; R₅ is C₁ alkyl substituted withR₈; and R₈ is cycloalkyl.
 30. A compound of claim 29, wherein thecycloalkyl is substituted with fluorine.
 31. A compound of claim 11,wherein R₅ is chosen from:


32. A composition of 14, wherein the compound is chosen from:


33. A composition of claim 23, wherein R₇ is H or Cl.
 34. A compositionof claim 24, wherein R₇ is H or Cl; and R₁ is pyridine.
 35. Acomposition of claim 23, wherein R₇ is H or Cl; R₆ is CH₃; R₅ is C₁alkyl substituted with R₈; and R₈ is cycloalkyl.
 36. A composition ofclaim 34, wherein the cycloalkyl is substituted with fluorine.
 37. Acomposition of claim 23, wherein R₅ is chosen from:


38. A compound of claim 1, having a structure represented by a formula:

wherein R₄ and R₅ cyclize to form a 3-8 membered ring containing C, O, Sor N, optionally substituted with one or more R₈; wherein R₆ is selectedfrom: H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, aryl, heteroaryl optionallysubstituted with one or more R₈; and wherein R₈, when present, isselected from OH, NR₁R₂, halogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, CN,OC₁₋₆ alkyl, or CF₃ and wherein W, X, Y, and Z are C or CH; R₇ is H orhalogen; A is O; and R₁ is pyridine.
 39. The compound of claim 1,wherein R₈ is —NH₂, —NHalkyl, or —NHcycloalkyl.
 40. The composition ofclaim 14, wherein R₈ is —NH₂, —NHalkyl, or —NHcycloalkyl.